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  • 1. Besevic, Jelena
    et al.
    Gunter, Marc J.
    Fortner, Renee T.
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Onland-Moret, N. Charlotte
    Dossus, Laure
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    Mesrine, Sylvie
    Baglietto, Laura
    Clavel-Chapelon, Francoise
    Kaaks, Rudolf
    Aleksandrova, Krasimira
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Bamia, Christina
    Masala, Giovanna
    Agnoli, Claudia
    Tumino, Rosario
    Ricceri, Fulvio
    Panico, Salvatore
    Bueno-de-Mesquita, H. B. (as)
    Peeters, Petra H.
    Jareid, Mie
    Ramon Quiros, J.
    Duell, Eric J.
    Sanchez, Maria-Jose
    Larranaga, Nerea
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Dias, Joana A.
    Sonestedt, Emily
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wareham, Nicholas J.
    Khaw, Kay-Tee
    Travis, Ruth C.
    Rinaldi, Sabina
    Romieu, Isabelle
    Riboli, Elio
    Merritt, Melissa A.
    Reproductive factors and epithelial ovarian cancer survival in the EPIC cohort study2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 113, no 11, p. 1622-1631Article in journal (Refereed)
    Abstract [en]

    Background: Reproductive factors influence the risk of developing epithelial ovarian cancer (EOC), but little is known about their association with survival. We tested whether prediagnostic reproductive factors influenced EOC-specific survival among 1025 invasive EOC cases identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which included 521 330 total participants (approximately 370 000 women) aged 25-70 years at recruitment from 1992 to 2000. Methods: Information on reproductive characteristics was collected at recruitment. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and multivariable models were adjusted for age and year of diagnosis, body mass index, tumour stage, smoking status and stratified by study centre. Results: After a mean follow-up of 3.6 years (+/- 3.2 s.d.) following EOC diagnosis, 511 (49.9%) of the 1025 women died from EOC. We observed a suggestive survival advantage in menopausal hormone therapy (MHT) users (ever vs never use, HR = 0.80, 95% CI = 0.62-1.03) and a significant survival benefit in long-term MHT users (>= 5 years use vs never use, HR = 0.70, 95% CI = 0.50-0.99, P-trend = 0.04). We observed similar results for MHT use when restricting to serous cases. Other reproductive factors, including parity, breastfeeding, oral contraceptive use and age at menarche or menopause, were not associated with EOC-specific mortality risk. Conclusions: Further studies are warranted to investigate the possible improvement in EOC survival in MHT users.

  • 2. Braem, Marieke G. M.
    et al.
    Onland-Moret, N. Charlotte
    Schouten, Leo J.
    Kruitwagen, Roy F. P. M.
    Lukanova, Annekatrin
    Allen, Naomi E.
    Wark, Petra A.
    Tjonneland, Anne
    Hansen, Louise
    Brauner, Christina Marie
    Overvad, Kim
    Clavel-Chapelon, Francoise
    Chabbert-Buffet, Nathalie
    Teucher, Birgit
    Floegel, Anna
    Boeing, Heiner
    Trichopoulou, Antonia
    Adarakis, George
    Plada, Maria
    Rinaldi, Sabina
    Fedirko, Veronika
    Romieu, Isabelle
    Pala, Valeria
    Galasso, Rocco
    Sacerdote, Carlotta
    Palli, Domenico
    Tumino, Rosario
    Bueno-de-Mesquita, H. Bas
    Gram, Inger Torhild
    Gavrilyuk, Oxana
    Lund, Eiliv
    Sanchez, Maria-Jose
    Bonet, Catalina
    Chirlaque, Maria-Dolores
    Larranaga, Nerea
    Barricarte Gurrea, Aurelio
    Quiros, Jose R.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jirstrom, Karin
    Butt, Salma
    Tsilidis, Konstantinos K.
    Khaw, Kay-Tee
    Wareham, Nick
    Riboli, Elio
    Kaaks, Rudolf
    Peeters, Petra H. M.
    Multiple Miscarriages Are Associated with the Risk of Ovarian Cancer: Results from the European Prospective Investigation into Cancer and Nutrition2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e37141-Article in journal (Refereed)
    Abstract [en]

    While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR >= 4vs.0: 1.74, 95% CI: 1.20-2.70; number of cases in this category: n = 23). This association was particularly evident for multiple miscarriages (HR >= 4vs.0: 1.99, 95% CI: 1.06-3.73; number of cases in this category: n = 10), with no significant association for multiple induced abortions (HR >= 4vs.0: 1.46, 95% CI: 0.68-3.14; number of cases in this category: n = 7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories.

  • 3. Braem, Marieke G. M.
    et al.
    Onland-Moret, N. Charlotte
    Schouten, Leo J.
    Tjonneland, Anne
    Hansen, Louise
    Dahm, Christina C.
    Overvad, Kim
    Lukanova, Annekatrin
    Dossus, Laure
    Floegel, Anna
    Boeing, Heiner
    Clavel-Chapelon, Francoise
    Chabbert-Buffet, Nathalie
    Fagherazzi, Guy
    Trichopoulou, Antonia
    Benetou, Vassiliki
    Goufa, Ioulia
    Pala, Valeria
    Galasso, Rocco
    Mattiello, Amalia
    Sacerdote, Carlotta
    Palli, Domenico
    Tumino, Rosario
    Gram, Inger T.
    Lund, Eiliv
    Gavrilyuk, Oxana
    Sanchez, Maria-Jose
    Quiros, Ramon
    Gonzales, Carlos A.
    Dorronsoro, Miren
    Huerta Castano, Jose M.
    Barricarte Gurrea, Aurelio
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jirstrom, Karin
    Witfalt, Elisabet
    Allen, Naomi E.
    Tsilidis, Konstantinos K.
    Kaw, Kay-Tee
    Bueno-de-Mesquita, H. Bas
    Dik, Vincent K.
    Rinaldi, Sabina
    Fedirko, Veronika
    Norat, Teresa
    Riboli, Elio
    Kaaks, Rudolf
    Peeters, Petra H. M.
    Coffee and tea consumption and the risk of ovarian cancer: a prospective cohort study and updated meta-analysis2012In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 95, no 5, p. 1172-1181Article in journal (Refereed)
    Abstract [en]

    Background: In 2007 the World Cancer Research Fund Report concluded that there was limited and inconsistent evidence for an effect of coffee and tea consumption on the risk of epithelial ovarian cancer (EOC). Objective: In the European Prospective Investigation into Cancer and Nutrition (EPIC), we aimed to investigate whether coffee intakes, tea intakes, or both are associated with the risk of EOC. Design: All women participating in the EPIC (n = 330,849) were included in this study. Data on coffee and tea consumption were collected through validated food-frequency questionnaires at baseline. HRs and 95% CIs were estimated by using Cox proportional hazards models. Furthermore, we performed an updated meta-analysis of all previous prospective studies until April 2011 by comparing the highest and lowest coffee- and tea-consumption categories as well as by using dose-response random-effects meta-regression analyses. Results: During a median follow-up of 11.7 y, 1244 women developed EOC. No association was observed between the risk of EOC and coffee consumption [HR: 1.05 (95% CI: 0.75, 1.46) for the top quintile compared with no intake] or tea consumption [HR: 1.07 (95% Cl: 0.78, 1.45) for the top quintile compared with no intake]. This lack of association between coffee and tea intake and EOC risk was confirmed by the results of our meta-analysis. Conclusion: Epidemiologic studies do not provide sufficient evidence to support an association between coffee and tea consumption and risk of ovarian cancer. Am J Clin Nutr 2012;95:1172-81.

  • 4. Broeze, KA
    et al.
    Opmeer, BC
    Coppus, SFPJ
    Van Geloven, N
    Alves, MFC
    Anestad, G
    Bhattacharya, S
    Allan, J
    Guerra-Infante, MF
    Den Hartog, JE
    Land, JA
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Van der Linden, PJQ
    Mouton, JW
    Ng, EHY
    Van der Steeg, JW
    Steures, P
    Svenstrup, HF
    Tiitinen, A
    Toye, B
    Van der Veen, F
    Mol, BW
    Chlamydia antibody testing and diagnosing tubal pathology in subfertile women: an individual patient data meta-analysis2011In: Human Reproduction Update, ISSN 1355-4786, E-ISSN 1460-2369, Vol. 17, no 3, p. 301-310Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The Chlamydia IgG antibody test (CAT) shows considerable variations in reported estimates of test accuracy, partly because of the use of different assays and cut-off values. The aim of this study was to reassess the accuracy of CAT in diagnosing tubal pathology by individual patient data (IPD) meta-analysis for three different CAT assays.

    METHODS We approached authors of primary studies that used micro-immunofluorescence tests (MIF), immunofluorescence tests (IF) or enzyme-linked immunosorbent assay tests (ELISA). Using the obtained IPD, we performed pooled receiver operator characteristics analysis and logistic regression analysis with a random effects model to compare the three assays. Tubal pathology was defined as either any tubal obstruction or bilateral tubal obstruction.

    RESULTS We acquired data of 14 primary studies containing data of 6191 women, of which data of 3453 women were available for analysis. The areas under the curve for ELISA, IF and MIF were 0.64, 0.65 and 0.75, respectively (P-value < 0.001) for any tubal pathology and 0.66, 0.66 and 0.77, respectively (P-value = 0.01) for bilateral tubal pathology.

    CONCLUSIONS In Chlamydia antibody testing, MIF is superior in the assessment of tubal pathology. In the initial screen for tubal pathology MIF should therefore be the test of first choice.

  • 5. Chen, Dan
    et al.
    Hammer, Joanna
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Gyllensten, Ulf
    A variant upstream of HLA-DRB1 and multiple variants in MICA influence susceptibility to cervical cancer in a Swedish population2014In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 3, no 1, p. 190-198Article in journal (Refereed)
    Abstract [en]

    In a genome-wide association study, we have previously identified and performed the initial replication of three novel susceptibility loci for cervical cancer: rs9272143 upstream of HLA-DRB1, rs2516448 adjacent to MHC class I polypeptide-related sequence A gene (MICA), and rs3117027 at HLA-DPB2. The risk allele T of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) in MICA exon 5, which results in a truncated protein. To validate these associations in an independent study and extend our prior work to MICA exon 5, we genotyped the single-nucleotide polymorphisms at rs9272143, rs2516448, rs3117027 and the MICA exon 5 microsatellite in a nested case–control study of 961 cervical cancer patients (827 carcinoma in situ and 134 invasive carcinoma) and 1725 controls from northern Sweden. The C allele of rs9272143 conferred protection against cervical cancer (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.65–0.82; P = 1.6 × 10−7), which is associated with higher expression level of HLA-DRB1, whereas the T allele of rs2516448 increased the susceptibility to cervical cancer (OR = 1.33, 95% CI = 1.19–1.49; P = 5.8 × 10−7), with the same association shown with MICA-A5.1. The direction and the magnitude of these associations were consistent with our previous findings. We also identified protective effects of the MICA-A4 (OR = 0.80, 95% CI = 0.68–0.94; P = 6.7 × 10−3) and MICA-A5 (OR = 0.60, 95% CI = 0.50–0.72; P = 3.0 × 10−8) alleles. The associations with these variants are unlikely to be driven by the nearby human leukocyte antigen (HLA) alleles. No association was observed between rs3117027 and risk of cervical cancer. Our results support the role of HLA-DRB1 and MICA in the pathogenesis of cervical cancer.

  • 6. Clendenen, Tess V
    et al.
    Arslan, Alan A
    Lokshin, Anna E
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Koenig, Karen L
    Marrangoni, Adele M
    Nolen, Brian M
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zeleniuch-Jacquotte, Anne
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Temporal reliability of cytokines and growth factors in EDTA plasma2010In: BMC research notes, ISSN 1756-0500, Vol. 3, no 1, p. 302-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cytokines are involved in the development of chronic diseases, including cancer. It is important to evaluate the temporal reproducibility of cytokines in plasma prior to conducting epidemiologic studies utilizing these markers.

    FINDINGS: We assessed the temporal reliability of CRP, 22 cytokines and their soluble receptors (IL-1alpha, IL-1beta, IL-1Ra, IL-2, sIL-2R, IL-4, IL-5, IL-6, sIL-6R, IL-7, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, TNFalpha, sTNF-R1, sTNF-R2, IFNalpha, IFNgamma) and eight growth factors (GM-CSF, EGF, bFGF, G-CSF, HGF, VEGF, EGFR, ErbB2) in repeated EDTA plasma samples collected an average of two years apart from 18 healthy women (age range: 42-62) enrolled in a prospective cohort study. We also estimated the correlation between serum and plasma biomarker levels using 18 paired clinical samples from postmenopausal women (age range: 75-86). Twenty-six assays were able to detect their analytes in at least 70% of samples. Of those 26 assays, we observed moderate to high intra-class correlation coefficients (ICCs)(ranging from 0.53-0.89) for 22 assays, and low ICCs (0-0.47) for four assays. Serum and plasma levels were highly correlated (r > 0.6) for most markers, except for seven assays (r < 0.5).

    CONCLUSIONS: For 22 of the 31 biomarkers, a single plasma measurement is a reliable estimate of a woman's average level over a two-year period.

  • 7. Clendenen, Tess V.
    et al.
    Arslan, Alan A.
    Lokshin, Anna E.
    Liu, Mengling
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Koenig, Karen L.
    Berrino, Franco
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Krogh, Vittorio
    Lukanova, Annekatrin
    Marrangoni, Adele
    Muti, Paola
    Nolen, Brian M.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Shore, Roy E.
    Sieri, Sabina
    Zeleniuch-Jacquotte, Anne
    Circulating prolactin levels and risk of epithelial ovarian cancer2013In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, no 4, p. 741-748Article in journal (Refereed)
    Abstract [en]

    Indirect evidence from experimental and epidemiological studies suggests that prolactin may be involved in ovarian cancer development. However, the relationship between circulating prolactin levels and risk of ovarian cancer is unknown.

    We conducted a nested case-control study of 230 cases and 432 individually matched controls within three prospective cohorts to evaluate whether pre-diagnostic circulating prolactin is associated with subsequent risk of ovarian cancer. We also assessed whether lifestyle and reproductive factors are associated with circulating prolactin among controls.

    Prolactin levels were significantly lower among post- versus pre-menopausal women, parous versus nulliparous women, and past versus never users of oral contraceptives in our cross-sectional analysis of controls. In our nested case-control study, we observed a non-significant positive association between circulating prolactin and ovarian cancer risk (ORQ4vsQ1 1.56, 95 % CI 0.94, 2.63, p trend 0.15). Our findings were similar in multivariate-adjusted models and in the subgroup of women who donated blood a parts per thousand yen5 years prior to diagnosis. We observed a significant positive association between prolactin and risk for the subgroup of women with BMI a parts per thousand yen25 kg/m(2) (ORQ4vsQ1 3.10, 95 % CI 1.39, 6.90), but not for women with BMI < 25 kg/m(2) (ORQ4vsQ1 0.81, 95 % CI 0.40, 1.64).

    Our findings suggest that prolactin may be associated with increased risk of ovarian cancer, particularly in overweight/obese women. Factors associated with reduced risk of ovarian cancer, such as parity and use of oral contraceptives, were associated with lower prolactin levels, which suggests that modulation of prolactin may be a mechanism underlying their association with risk.

  • 8. Clendenen, Tess V.
    et al.
    Hertzmark, Kathryn
    Koenig, Karen L.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rinaldi, Sabina
    Johnson, Theron
    Krogh, Vittorio
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Lukanova, Annekatrin
    Zeleniuch-Jacquotte, Anne
    Premenopausal Circulating Androgens and Risk of Endometrial Cancer: results of a Prospective Study2016In: Hormones & cancer, ISSN 1868-8500, Vol. 7, no 3, p. 178-187Article in journal (Refereed)
    Abstract [en]

    Endometrial cancer risk is increased by estrogens unopposed by progesterone. In premenopausal women, androgen excess is often associated with progesterone insufficiency, suggesting that premenopausal androgen concentrations may be associated with risk. In a case-control study nested within three cohorts, we assessed the relationship between premenopausal androgens and risk of endometrial cancer (161 cases and 303 controls matched on age and date of blood donation). Testosterone, DHEAS, androstenedione, and SHBG were measured in serum or plasma. Free testosterone was calculated from testosterone and SHBG. We observed trends of increasing risk across tertiles of testosterone (ORT3-T1 = 1.59, 95 % CI = 0.96, 2.64, p = 0.08) and free testosterone (ORT3-T1 = 1.76, 95 % CI = 1.01, 3.07, p = 0.047), which were not statistically significant after adjustment for body mass index (BMI). There was no association for DHEAS, androstenedione, or SHBG. There were significant interactions by age at diagnosis (<55 years, n = 51 cases; ≥55 years, n = 110 cases). Among women who were ≥55 years of age (predominantly postmenopausal) at diagnosis, the BMI-adjusted OR was 2.08 (95 % CI = 1.25, 3.44, p = 0.005) for a doubling in testosterone and 1.55 (95 % CI = 1.04, 2.31, p = 0.049) for a doubling in free testosterone. There was no association among women aged <55 years at diagnosis, consistent with the only other prospective study to date. If pre- and post-menopausal concentrations of androgens are correlated, our observation of an association of premenopausal androgens with risk among women aged ≥55 years at diagnosis could be due to the effect on the endometrium of postmenopausal androgen-derived estrogens in the absence of progesterone, which is no longer secreted.

  • 9. Clendenen, Tess V
    et al.
    Koenig, Karen L
    Arslan, Alan A
    Lukanova, Annekatrin
    Berrino, Franco
    Gu, Yian
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Krogh, Vittorio
    Lokshin, Anna E
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Muti, Paola
    Marrangoni, Adele
    Nolen, Brian M
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Shore, Roy E
    Sieri, Sabina
    Zeleniuch-Jacquotte, Anne
    Factors associated with inflammation markers, a cross-sectional analysis2011In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 56, no 3, p. 769-778Article in journal (Refereed)
    Abstract [en]

    Epidemiological studies have reported associations between circulating inflammation markers and risk of chronic diseases. It is of interest to examine whether risk factors for these diseases are associated with inflammation. We conducted a cross-sectional analysis to evaluate whether reproductive and lifestyle factors and circulating vitamin D were associated with inflammation markers, including C-reactive protein, cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, TNFα), and cytokine modulators (IL-1RA, sIL-1RII, sIL-2Ra, sIL-4R, sIL-6R, sTNF-R1/R2), among 616 healthy women. We confirmed associations of several inflammation markers with age and BMI. We also observed significantly higher levels of certain inflammation markers in postmenopausal vs. premenopausal women (TNFα, sIL-1RII, sIL-2Ra), with increasing parity (IL-12p40), and with higher circulating 25(OH) vitamin D (IL-13) and lower levels among current users of non-steroidal anti-inflammatory drugs (NSAIDs) (IL-1β, IL-2, IL-10, IL-12p70, and IL-12p40), current smokers (IL-4, IL-13, IL-12p40), and women with a family history of breast or ovarian cancer (IL-4, IL-10, IL-13). Our findings suggest that risk factors for chronic diseases (age, BMI, menopausal status, parity, NSAID use, family history of breast and ovarian cancer, and smoking) are associated with inflammation markers in healthy women.

  • 10. Clendenen, Tess V
    et al.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zeleniuch-Jacquotte, Anne
    Koenig, Karen L
    Berrino, Franco
    Lukanova, Annekatrin
    Lokshin, Anna E
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Krogh, Vittorio
    Sieri, Sabina
    Muti, Paola
    Marrangoni, Adele
    Nolen, Brian M
    Liu, Mengling
    Shore, Roy E
    Arslan, Alan A
    Circulating inflammation markers and risk of epithelial ovarian cancer.2011In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, no 5, p. 799-810Article in journal (Refereed)
    Abstract [en]

    Background: Factors contributing to chronic inflammation appear to be associated with increased risk of ovarian cancer. The purpose of this study was to assess the association between circulating levels of inflammation mediators and subsequent risk of ovarian cancer.

    Methods: We conducted a case-control study of 230 cases and 432 individually matched controls nested within three prospective cohorts to evaluate the association of prediagnostic circulating levels of inflammation-related biomarkers (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, TNFα, IL-1Ra, sIL-1RII, sIL-2Ra, sIL-4R, sIL-6R, sTNF-R1, and sTNF-R2) measured using Luminex xMap technology with risk of ovarian cancer.

    Results: We observed a trend across quartiles for IL-2 (ORQ4 vs. Q1: 1.57, 95% CI: 0.98–2.52, P = 0.07), IL-4 (ORQ4 vs. Q1: 1.50, 95% CI: 0.95–2.38, P = 0.06), IL-6 (ORQ4 vs. Q1: 1.63, 95% CI: 1.03–2.58, P = 0.03), IL-12p40 (ORQ4 vs. Q1: 1.60, 95% CI: 1.02–2.51, P = 0.06), and IL-13 (ORQ4 vs. Q1: 1.42, 95% CI: 0.90–2.26, P = 0.11). Trends were also observed when cytokines were modeled on the continuous scale for IL-4 (P trend = 0.01), IL-6 (P trend = 0.01), IL-12p40 (P trend = 0.01), and IL-13 (P trend = 0.04). ORs were not materially different after excluding cases diagnosed less than 5 years after blood donation or when limited to serous tumors.

    Conclusions and Impact: This study provides the first direct evidence that multiple inflammation markers, specifically IL-2, IL-4, IL-6, IL-12, and IL-13, may be associated with risk of epithelial ovarian cancer, and adds to the evidence that inflammation is involved in the development of this disease.

  • 11.
    Collins, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Strandell, Annika
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Menopausal symptoms and surgical complications after opportunistic bilateral salpingectomy, a register-based cohort study2019In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 220, no 1, article id 85.e1-e10Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In recent years, the fallopian tubes have been found to play a critical role in the pathogenesis of ovarian cancer. Therefore, bilateral salpingectomy at the time of hysterectomy has been proposed as a preventive procedure, but with scarce scientific evidence to support the efficiency and safety. OBJECTIVE: Our primary objective was to evaluate the risk of surgical complications and menopausal symptoms when performing bilateral salpingectomy in addition to benign hysterectomy. Furthermore, we sought to compare time in surgery, perioperative blood loss/blood transfusion, duration of hospital stay, days to normal activities of daily living, and days out of work for hysterectomy with bilateral salpingectomy compared with hysterectomy only. A secondary objective was to study the uptake of opportunistic salpingectomy in Sweden. STUDY DESIGN: This was a retrospective observational cohort study based on data from the National Quality Register of Gynecological Surgery in Sweden. Women <55 years of age who had a hysterectomy for benign indications with or without bilateral salpingectomy in 1998 through 2016 were included. Possible confounding was adjusted for in multivariable regression models. RESULTS: During the study period, 23,369 women had a hysterectomy for benign indications. The frequency of bilateral salpingectomy at the time of hysterectomy increased mainly from 2013, which is why the period 2013 through mid-2016 was selected for further analysis (n = 6892). There was a low frequency of vaginal hysterectomy with bilateral salpingectomy performed in this period, which is why only abdominal and laparoscopic surgeries were selected for comparative analysis (n = 4906). This study indicates an increased risk of menopausal symptoms (adjusted relative risk, 1.33; 95% confidence interval, 1.04-1.69) 1 year after hysterectomy with bilateral salpingectomy compared with hysterectomy only. Hospital stay was 0.1 days longer in women having salpingectomy (P = .01), and bleeding was slightly reduced in the salpingectomy group (-20 mL, P = .04). Other outcome measures were not significantly associated with salpingectomy, albeit a tendency toward higher risk of minor complications was seen (adjusted relative risk, 1.30; 95% confidence interval, 0.93-1.83). CONCLUSION: Bilateral salpingectomy at the time of hysterectomy was associated with an increased risk of menopausal symptoms 1 year after surgery. Randomized clinical trials reducing the risk of residual and unmeasured confounding and longer follow-up are needed to correctly inform women on the risks and benefits of opportunistic salpingectomy.

  • 12. Cramer, Daniel W.
    et al.
    Fichorova, Raina N.
    Terry, Kathryn L.
    Yamamoto, Hidemi
    Vitonis, Allison F.
    Ardanaz, Eva
    Aune, Dagfinn
    Boeing, Heiner
    Brändstedt, Jenny
    Boutron-Ruault, Marie-Christine
    Chirlaque, Maria-Dolores
    Dorronsoro, Miren
    Dossus, Laure
    Duell, Eric J.
    Gram, Inger T.
    Gunter, Marc
    Hansen, Louise
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Johnson, Theron
    Khaw, Kay-Tee
    Krogh, Vittorio
    Kvaskoff, Marina
    Mattiello, Amalie
    Matullo, Giuseppe
    Merritt, Melissa A.
    Nodin, Björn
    Orfanos, Philippos
    Onland-Moret, N. Charlotte
    Palli, Domenico
    Peppa, Eleni
    Quirós, J. Ramón
    Sánchez-Perez, Maria-Jose
    Severi, Gianluca
    Tjønneland, Anne
    Travis, Ruth C.
    Trichopoulou, Antonia
    Tumino, Rosario
    Weiderpass, Elisabete
    Fortner, Renée T.
    Kaaks, Rudolf
    Anti-CA15.3 and Anti-CA125 Antibodies and Ovarian Cancer Risk: Results from the EPIC Cohort2018In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 27, no 7, p. 790-804Article in journal (Refereed)
    Abstract [en]

    Background: Neoplastic and non-neoplastic events may raise levels of mucins, CA15.3, and CA125, and generate antibodies against them, but their impact on epithelial ovarian cancer (FOC) risk has not been fully defined.

    Methods: CA15.3, CA125, and IgC1 antibodies against them were measured in 806 women who developed FAN; and 1,927 matched controls from the European Prospective Investigation of Nutrition and Cancer. Associations between epidemiologic factors and anti-mucin antibodies were evaluated using generalized linear models; EOC risks associated with anti-mucin antibodies, by themselves or in combination with respective antigens, were evaluated using conditional logistic regression.

    Results: In controls, lower antibodies against both mucins were associated with current smoking; and, in postmenopausal women, higher levels with longer oral contraceptive use and later-age-at and shorter-interval-since last birth. Lower antiCA15.3 antibodies were associated with higher body mass and, in premenopausal women, more ovulatory cycles. Higher anti-CA15.3 and anti-CA In antibodies were associated with higher risk for mutinous IOC occurring >= 3 years from enrollment. Long-term risk for serous EOC was reduced in women with low CA125 and high anti-CA125 antibodies relative to women with low concentrations of both.

    Conclusions: We found general support for the hypothesis that anti-mucin antibody levels correlate with risk factors for EOC Antibodies alone or in combinations with their antigen may predict longer term risk of specific EOC types.

    Impact: Anti-CA125 and anti-CA15.3 antibodies alone or in perspective of antigens may be informative in the pathogenesis of EOC subtypes, but less useful for informing risk for all EOC.

  • 13.
    Dossus, Laure
    et al.
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Becker, Susen
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Rinaldi, Sabina
    Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
    Lukanova, Annekatrin
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Tjønneland, Anne
    Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
    Olsen, Anja
    Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
    Overvad, Kim
    Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark.
    Chabbert-Buffet, Nathalie
    Department of Obstetrics and Gynecology, APHP Hospital Tenon and UMPC, Paris, France.
    Boutron-Ruault, Marie-Christine
    INSERM, Centre for Research in Epidemiology and Population Health, Paris South University, Gustave Roussy Institute, Villejuif, France.
    Clavel-Chapelon, Françoise
    INSERM, Centre for Research in Epidemiology and Population Health, Paris South University, Gustave Roussy Institute, Villejuif, France.
    Teucher, Birgit
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Chang-Claude, Jenny
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Pischon, Tobias
    Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
    Boeing, Heiner
    Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
    Trichopoulou, Antonia
    Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece.
    Benetou, Vasiliki
    Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece.
    Valanou, Elisavet
    Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece.
    Palli, Domenico
    Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy.
    Sieri, Sabina
    Department of Preventive and Predictive Medicine, Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
    Tumino, Rosario
    Cancer Registry and Histopathology Unit, “Civile – M.P. Arezzo” Hospital, Ragusa, Italy.
    Sacerdote, Carlotta
    Center for Cancer Prevention (CPO Piedmont), Turin, Italy.
    Galasso, Rocco
    Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS-CROOB), Rionero in Vulture (PZ), Italy.
    Redondo, Maria-Luísa
    Public Health and Participation Directorate, Health and Health Care Services Council, Asturias, Spain.
    Bonet Bonet, Catalina
    Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO), Barcelona, Spain.
    Molina-Montes, Esther
    Andalusian School of Public Health, Granada, Spain.
    Altzibar, Jone M
    CIBER de Epidemiología y Salud Pública (CIBERESP), Spain.
    Chirlaque, Maria-Dolores
    CIBER de Epidemiología y Salud Pública (CIBERESP), Spain.
    Ardanaz, Eva
    CIBER de Epidemiología y Salud Pública (CIBERESP), Spain.
    Bueno-de-Mesquita, H Bas
    CIBER de Epidemiología y Salud Pública (CIBERESP), Spain.
    van Duijnhoven, Fränzel J B
    National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
    Peeters, Petra H M
    Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.
    Onland-Moret, N Charlotte
    Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Khaw, Kay-Tee
    Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Wareham, Nicholas
    MRC Epidemiology Unit, Cambridge, United Kingdom.
    Allen, Naomi
    Nuffield Department of Clinical Medicine, Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
    Romieu, Isabelle
    International Agency for Research on Cancer, Lyon, France.
    Fedirko, Veronika
    International Agency for Research on Cancer, Lyon, France.
    Hainaut, Pierre
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom.
    Romaguera, Dora
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom.
    Norat, Teresa
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom.
    Riboli, Elio
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom.
    Kaaks, Rudolf
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Tumor necrosis factor (TNF)-α, soluble TNF receptors and endometrial cancer risk: the EPIC study2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 129, no 8, p. 2032-2037Article in journal (Refereed)
    Abstract [en]

    Chronic inflammation has been hypothesized to play a role in endometrial cancer development. Tumor necrosis factor-α (TNF-α), one of the major pro-inflammatory cytokines, has also been implicated in endometrial physiology. We conducted a case-control study nested within the European prospective investigation into cancer and nutrition (EPIC) to examine the association of TNF-α and its two soluble receptors (sTNFR1 and sTNFR2) with endometrial cancer risk. Two-hundred-seventy cases and 518 matched controls were analyzed using conditional logistic regression. All statistical tests were two-sided. We observed an increased risk of endometrial cancer among women in the highest versus lowest quartile of TNF-α (odds ratio [OR]: 1.73, 95% CI: 1.09-2.73, Ptrend = 0.01), sTNFR1 (OR: 1.68, 95% CI: 0.99-2.86, Ptrend = 0.07) and sTNFR2 (OR: 1.53, 95%CI: 0.92-2.55, Ptrend = 0.03) after adjustment for body-mass-index, parity, age at menopause and previous postmenopausal hormone therapy use. Further adjustments for estrogens and C-peptide had minor effect on risk estimates. Our data show that elevated prediagnostic concentrations of TNF-α and its soluble receptors are related to a higher risk of endometrial cancer, particularly strong in women diagnosed within 2 years of blood donation. This is the first study of its kind and therefore deserves replication in further prospective studies.

  • 14. Fedirko, Veronika
    et al.
    Jenab, Mazda
    Rinaldi, Sabina
    Biessy, Carine
    Allen, Naomi E.
    Dossus, Laure
    Onland-Moret, N. Charlotte
    Schuetze, Madlen
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    Clavel-Chapelon, Francoise
    Chabbert-Buffet, Nathalie
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Bergmann, Manuela M.
    Boeing, Heiner
    Trichopoulou, Antonia
    Oustoglou, Erifili
    Barbitsioti, Antonia
    Saieva, Calogero
    Tagliabue, Giovanna
    Galasso, Rocco
    Tumino, Rosario
    Sacerdote, Carlotta
    Peeters, Petra H.
    Bueno-de-Mesquita, H. Bas
    Weiderpass, Elisabete
    Gram, Inger Torhild
    Sanchez, Soledad
    Duell, Eric J.
    Molina-Montes, Esther
    Arriola, Larraitz
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Manjer, Jonas
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Khaw, Kay-Tee
    Romaguera-Bosch, Dora
    Wark, Petra A.
    Norat, Teresa
    Romieu, Isabelle
    Alcohol drinking and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study2013In: Annals of Epidemiology, ISSN 1047-2797, E-ISSN 1873-2585, Vol. 23, no 2, p. 93-98Article in journal (Refereed)
    Abstract [en]

    Purpose: Alcohol intake may adversely affect the concentrations of endogenous sex hormones, and thus increase the risk of endometrial cancer. However, epidemiologic studies have provided conflicting results. Therefore, we investigated the association between alcohol intake and endometrial cancer risk a large, multicenter, prospective study. Methods: From 1992 through 2010, 301,051 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were followed for incident endometrial cancer (n = 1382). Baseline alcohol consumption was assessed by country-specific, validated dietary questionnaires. Information on past alcohol consumption was collected by lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models. Results: The multivariable HRs (and 95% CIs) compared with light drinkers (0.1-6 g/d) were 1.03(0.88-1.20) for 0 g of alcohol per day at baseline, 1.01 (0.86-1.17) for 6.1-12 g/d, 1.03 (0.87-1.22) for 12.1-24 g/d, 1.07(0.87-1.38) for 241-36 g/d, and 0.85(0.61-1.18) for more than 36 g/d (p(trend) = 0.77). No association was observed among former drinkers (OR, 1.28; 95% CI, 0.98-1.68 compared with light drinkers). Null associations were also found between alcohol consumption at age 20 years, lifetime pattern of alcohol drinking, and baseline alcohol intake from specific alcoholic beverages and endometrial cancer risk. Conclusions: Our findings suggest no association between alcohol intake and endometrial cancer risk.

  • 15. Fortner, Renee T.
    et al.
    Huesing, Anika
    Kuehn, Tilman
    Konar, Meric
    Overvad, Kim
    Tjonneland, Anne
    Hansen, Louise
    Boutron-Ruault, Marie-Christine
    Severi, Gianluca
    Fournier, Agnes
    Boeing, Heiner
    Trichopoulou, Antonia
    Benetou, Vasiliki
    Orfanos, Philippos
    Masala, Giovanna
    Agnoli, Claudia
    Mattiello, Amalia
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-de-Mesquita, H. B(as)
    Peeters, Petra H. M.
    Weiderpass, Elisabete
    Gram, Inger T.
    Gavrilyuk, Oxana
    Ramon Quiros, J.
    Maria Huerta, Jose
    Ardanaz, Eva
    Larranaga, Nerea
    Lujan-Barroso, Leila
    Sanchez-Cantalejo, Emilio
    Butt, Salma Tuna
    Borgquist, Signe
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Allen, Naomi E.
    Rinaldi, Sabina
    Dossus, Laure
    Gunter, Marc
    Merritt, Melissa A.
    Tzoulaki, Ioanna
    Riboli, Elio
    Kaaks, Rudolf
    Endometrial cancer risk prediction including serum-based biomarkers: results from the EPIC cohort2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 6, p. 1317-1323Article in journal (Refereed)
    Abstract [en]

    Endometrial cancer risk prediction models including lifestyle, anthropometric and reproductive factors have limited discrimina-tion. Adding biomarker data to these models may improve predictive capacity; to our knowledge, this has not been investigat-ed for endometrial cancer. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the improvement in discrimination gained by adding serum biomarker concentrations to risk estimates derived from an existing risk prediction model based on epidemiologic factors. Serum concentrations of sex steroid hormones, metabolic markers, growth factors, adipokines and cytokines were evaluated in a step-wise backward selec-tion process; biomarkers were retained at p < 0.157 indicating improvement in the Akaike information criterion (AIC). Improvement in discrimination was assessed using the C-statistic for all biomarkers alone, and change in C-statistic from addition of biomarkers to preexisting absolute risk estimates. We used internal validation with bootstrapping (1000-fold) to adjust for over-fitting. Adiponectin, estrone, interleukin-1 receptor antagonist, tumor necrosis factor-alpha and triglycerides were select-ed into the model. After accounting for over-fitting, discrimination was improved by 2.0 percentage points when all evaluated biomarkers were included and 1.7 percentage points in the model including the selected biomarkers. Models including eti-ologic markers on independent pathways and genetic markers may further improve discrimination.

  • 16. Fortner, Renee T.
    et al.
    Ose, Jennifer
    Merritt, Melissa A.
    Schock, Helena
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    Dossus, Laure
    Clavel-Chapelon, Francoise
    Baglietto, Laura
    Boeing, Heiner
    Trichopoulou, Antonia
    Benetou, Vassiliki
    Lagiou, Pagona
    Agnoli, Claudia
    Mattiello, Amalia
    Masala, Giovanna
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-de-Mesquita, H. B(as)
    Onland-Moret, N. Charlotte
    Peeters, Petra H.
    Weiderpass, Elisabete
    Gram, Inger Torhild
    Duell, Eric J.
    Larranaga, Nerea
    Ardanaz, Eva
    Sanchez, Maria-Jose
    Chirlaque, M-D
    Braendstedt, Jenny
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C.
    Rinaldi, Sabina
    Romieu, Isabelle
    Gunter, Marc J.
    Riboli, Elio
    Kaaks, Rudolf
    Reproductive and hormone-related risk factors for epithelial ovarian cancer by histologic pathways, invasiveness and histologic subtypes: results from the EPIC cohort2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 5, p. 1196-1208Article in journal (Refereed)
    Abstract [en]

    Whether risk factors for epithelial ovarian cancer (EOC) differ by subtype (i.e., dualistic pathway of carcinogenesis, histologic subtype) is not well understood; however, data to date suggest risk factor differences. We examined associations between reproductive and hormone-related risk factors for EOC by subtype in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Among 334,126 women with data on reproductive and hormone-related risk factors (follow-up: 1992-2010), 1,245 incident cases of EOC with known histology and invasiveness were identified. Data on tumor histology, grade, and invasiveness, were available from cancer registries and pathology record review. We observed significant heterogeneity by the dualistic model (i.e., type I [low grade serous or endometrioid, mucinous, clear cell, malignant Brenner] vs. type II [high grade serous or endometrioid]) for full-term pregnancy (p(het)=0.02). Full-term pregnancy was more strongly inversely associated with type I than type II tumors (ever vs. never: type I: relative risk (RR) 0.47 [95% confidence interval (CI): 0.33-0.69]; type II, RR: 0.81 [0.61-1.06]). We observed no significant differences in risk in analyses by major histologic subtypes of invasive EOC (serous, mucinous, endometrioid, clear cell). None of the investigated factors were associated with borderline tumors. Established protective factors, including duration of oral contraceptive use and full term pregnancy, were consistently inversely associated with risk across histologic subtypes (e.g., ever full-term pregnancy: serous, RR: 0.73 [0.58-0.92]; mucinous, RR: 0.53 [0.30-0.95]; endometrioid, RR: 0.65 [0.40-1.06]; clear cell, RR: 0.34 [0.18-0.64]; p(het)=0.16). These results suggest limited heterogeneity between reproductive and hormone-related risk factors and EOC subtypes. What's new? Reproductive and hormone-related risk factors for epithelial ovarian cancer (EOC) have been extensively investigated. However, EOC is increasingly recognized as a heterogeneous disease and risk factor differences across EOC subtypes, as defined by the recently proposed dualistic pathway of ovarian carcinogenesis and histological characteristics, are not well understood. Here, the authors present a detailed prospective investigation on reproductive and hormone-related risk factors for borderline tumors and epithelial ovarian cancer by main histological subtypes and, for the first time, by the types defined by the dualistic pathway. The results suggest limited heterogeneity between reproductive and hormone-related risk factors and EOC subtypes.

  • 17. Fortner, Renee T.
    et al.
    Poole, Elizabeth M.
    Wentzensen, Nicolas A.
    Trabert, Britton
    White, Emily
    Arslan, Alan A.
    Patel, Alpa, V
    Setiawan, V. Wendy
    Visvanathan, Kala
    Weiderpass, Elisabete
    Adami, Hans-Olov
    Black, Amanda
    Bernstein, Leslie
    Brinton, Louise A.
    Buring, Julie
    Clendenen, Tess, V
    Fournier, Agnes
    Fraser, Gary
    Gapstur, Susan M.
    Gaudet, Mia M.
    Giles, Graham G.
    Gram, Inger T.
    Hartge, Patricia
    Hoffman-Bolton, Judith
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Kaaks, Rudolf
    Kirsh, Victoria A.
    Knutsen, Synnove
    Koh, Woon-Puay
    Lacey, James V., Jr.
    Lee, I-Min
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Merritt, Melissa A.
    Milne, Roger L.
    Onland-Moret, N. Charlotte
    Peters, Ulrike
    Poynter, Jenny N.
    Rinaldi, Sabina
    Robien, Kim
    Rohan, Thomas
    Sanchez, Maria-Jose
    Schairer, Catherine
    Schouten, Leo J.
    Tjonneland, Anne
    Townsend, Mary K.
    Travis, Ruth C.
    Trichopoulou, Antonia
    van den Brandt, Piet A.
    Vineis, Paolo
    Wilkens, Lynne
    Wolk, Alicja
    Yang, Hannah P.
    Zeleniuch-Jacquotte, Anne
    Tworoger, Shelley S.
    Ovarian cancer risk factors by tumor aggressiveness: an analysis from the Ovarian Cancer Cohort Consortium2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 1, p. 58-69Article in journal (Refereed)
    Abstract [en]

    Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58–0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92–1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47–2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2, 1.93 [1.46–2.56] and current smoking (vs. never, 1.30 [1.07–1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.

  • 18. Fortner, Renee T.
    et al.
    Vitonis, Allison F.
    Schock, Helena
    Huesing, Anika
    Johnson, Theron
    Fichorova, Raina N.
    Fashemi, Titilayo
    Yamamoto, Hidemi S.
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Kvaskoff, Marina
    Severi, Gianluca
    Boeing, Heiner
    Trichopoulou, Antonia
    Benetou, Vassiliki
    La Vecchia, Carlo
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Matullo, Giuseppe
    Mattiello, Amalia
    Onland-Moret, N. Charlotte
    Peeters, Petra H.
    Weiderpass, Elisabete
    Gram, Inger Torhild
    Jareid, Mie
    Ramon Quiros, J.
    Duell, Eric J.
    Sanchez, Maria-Jose
    Dolores Chirlaque, Maria
    Ardanaz, Eva
    Larranaga, Nerea
    Nodin, Bjorn
    Brandstedt, Jenny
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Khaw, Kay-Tee
    Allen, Naomi
    Gunter, Marc
    Johansson, Mattias
    Dossus, Laure
    Merritt, Melissa A.
    Riboli, Elio
    Cramer, Daniel W.
    Kaaks, Rudolf
    Terry, Kathryn L.
    Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort2017In: Journal of Ovarian Research, ISSN 1757-2215, E-ISSN 1757-2215, Vol. 10, article id 20Article in journal (Refereed)
    Abstract [en]

    Background: Ovarian cancer early detection markers CA125, CA15.3, HE4, and CA72.4 vary between healthy women, limiting their utility for screening.

    Methods: We evaluated cross-sectional relationships between lifestyle and reproductive factors and these markers among controls (n = 1910) from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Improvements in discrimination of prediction models adjusting for correlates of the markers were evaluated among postmenopausal women in the nested case-control study (n = 590 cases). Generalized linear models were used to calculate geometric means of CA125, CA15.3, and HE4. CA72.4 above vs. below limit of detection was evaluated using logistic regression. Early detection prediction was modeled using conditional logistic regression.

    Results: CA125 concentrations were lower, and CA15.3 higher, in post- vs. premenopausal women (p ≤ 0.02). Among postmenopausal women, CA125 was higher among women with higher parity and older age at menopause (ptrend ≤ 0.02), but lower among women reporting oophorectomy, hysterectomy, ever use of estrogen-only hormone therapy, or current smoking (p < 0.01). CA15.3 concentrations were higher among heavier women and in former smokers (p ≤ 0.03). HE4 was higher with older age at blood collection and in current smokers, and inversely associated with OC use duration, parity, and older age at menopause (≤ 0.02). No associations were observed with CA72.4. Adjusting for correlates of the markers in prediction models did not improve the discrimination.

    Conclusions: This study provides insights into sources of variation in ovarian cancer early detection markers in healthy women and informs about the utility of individualizing marker cutpoints based on epidemiologic factors.

  • 19. Fortner, Renée T.
    et al.
    Schock, Helena
    Jung, Seungyoun
    Allen, Naomi E.
    Arslan, Alan A.
    Brinton, Louise A.
    Egleston, Brian L.
    Falk, Roni T.
    Gunter, Marc J.
    Helzlsouer, Kathy J.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Johnson, Theron S.
    Kaaks, Rudolf
    Krogh, Vittorio
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Merritt, Melissa A.
    Navarro, Carmen
    Onland-Moret, N. Charlotte
    Palli, Domenico
    Shu, Xiao-Ou
    Sluss, Patrick M.
    Staats, Paul N.
    Trichopoulou, Antonia
    Weiderpass, Elisabete
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Dorgan, Joanne F.
    Anti-Mullerian hormone and endometrial cancer: a multi-cohort study2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 117, no 9, p. 1412-1418Article in journal (Refereed)
    Abstract [en]

    Background: The Mullerian ducts are the embryological precursors of the female reproductive tract, including the uterus; anti-Mullerian hormone (AMH) has a key role in the regulation of foetal sexual differentiation. Anti-Mullerian hormone inhibits endometrial tumour growth in experimental models by stimulating apoptosis and cell cycle arrest. To date, there are no prospective epidemiologic data on circulating AMH and endometrial cancer risk. Methods: We investigated this association among women premenopausal at blood collection in a multicohort study including participants from eight studies located in the United States, Europe, and China. We identified 329 endometrial cancer cases and 339 matched controls. AntiMullerian hormone concentrations in blood were quantified using an enzyme-linked immunosorbent assay. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) across tertiles and for a doubling of AMH concentrations (ORlog2). Subgroup analyses were performed by ages at blood donation and diagnosis, oral contraceptive use, and tumour characteristics. Results: Anti-Mullerian hormone was not associated with the risk of endometrial cancer overall (ORlog(2): 1.07 (0.99-1.17)), or with any of the examined subgroups. Conclusions: Although experimental models implicate AMH in endometrial cancer growth inhibition, our findings do not support a role for circulating AMH in the aetiology of endometrial cancer.

  • 20. Fortner, Renée T.
    et al.
    Schock, Helena
    Le Cornet, Charlotte
    Hüsing, Anika
    Vitonis, Allison F.
    Johnson, Theron S.
    Fichorova, Raina N.
    Fashemi, Titilayo
    Yamamoto, Hidemi S.
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Kvaskoff, Marina
    Severi, Gianluca
    Boeing, Heiner
    Trichopoulou, Antonia
    Papatesta, Eleni-Maria
    La Vecchia, Carlo
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Onland-Moret, N. Charlotte
    Peeters, Petra H.
    Bueno-de-Mesquita, H. B(as)
    Weiderpass, Elisabete
    Quirós, J. Ramón
    Duell, Eric J.
    Sánchez, Maria-Jose
    Navarro, Carmen
    Ardanaz, Eva
    Larrañaga, Nerea
    Nodin, Björn
    Jirström, Karin
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Travis, Ruth C.
    Gunter, Marc
    Johansson, Mattias
    Dossus, Laure
    Merritt, Melissa A.
    Riboli, Elio
    Terry, Kathryn L.
    Cramer, Daniel W.
    Kaaks, Rudolf
    Ovarian cancer early detection by circulating CA125 in the context of anti-CA125 autoantibody levels: Results from the EPIC cohort2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 142, no 7, p. 1355-1360Article in journal (Refereed)
    Abstract [en]

    CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and non-cases. Anti-CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non-cases. We investigated these objectives using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to four matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2-year lag-time intervals were calculated using conditional logistic regression calibrated toward the absolute risk estimates from a pre-existing epidemiological risk model as an offset-variable. Anti-CA125 levels alone did not discriminate cases from controls. For cases diagnosed <2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti-CA125 levels (aAUC, highest antibody tertile: 0.84 [0.76-0.92]; lowest tertile: 0.76 [0.67-0.86]; p(het)=0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti-CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection. What's new? Although CA125, a mucin produced in epithelial cells, is a known marker for ovarian cancer, complementary biomarkers are necessary for reliable early cancer detection. Here, the authors examined autoantibodies against CA125 as potential pre-diagnosis markers. Although anti-CA125 levels did not discriminate between ovarian cases and controls, discrimination of CA125 differed by levels of its antibody, with the highest discrimination among women with the highest antibody levels. The authors propose that CA125 and anti-CA125 may act synergistically for ovarian cancer early detection.

  • 21. Gram, Inger T
    et al.
    Lukanova, Annekatrin
    Brill, Ilene
    Braaten, Tonje
    Lund, Eiliv
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Overvad, Kim
    Tjønneland, Anne
    Clavel-Chapelon, Francoise
    Chabbert-Buffet, Nathalie
    Bamia, Christina
    Trichopoulou, Antonia
    Zylis, Dimosthenis
    Masala, Giovanna
    Berrino, Franco
    Galasso, Rocco
    Tumino, Rosario
    Sacerdote, Carlotta
    Gavrilyuk, Oxana
    Kristiansen, Steinar
    Rodríguez, Laudina
    Bonet, Catalina
    Huerta, José María
    Barricarte, Aurelio
    Sánchez, Maria-José
    Dorronsoro, Miren
    Jirström, Karin
    Almquist, Martin
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Bueno-de-Mesquita, H Bas
    Braem, Marie
    Onland-Moret, Charlotte
    Tsilidis, Konstantinos K
    Allen, Naomi E
    Fedirko, Veronika
    Riboli, E
    Kaaks, Rudolf
    Cigarette smoking and risk of histological subtypes of epithelial ovarian cancer in the EPIC cohort study2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 9, p. 2204-2210Article in journal (Refereed)
    Abstract [en]

    New data regarding a positive association between smoking and risk of epithelial ovarian cancer (EOC), especially the mucinous tumor type, has started to emerge. The purpose of this study was to examine the association between different measures of smoking exposures and subtypes of EOC in a large cohort of women from 10 European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort is a multicenter prospective study initiated in 1992. The questionnaires included data about dietary, lifestyle, and health factors. Information about cigarette smoking was collected from individuals in all participating countries. We used Cox proportional hazard regression models to estimate hazard ratio (HR) of EOC overall and serous, mucinous, and endometroid histological subtypes, with 95% confidence intervals (CIs) associated with different measures of smoking exposures adjusting for confounding variables. Altogether 836 incident EOC cases were identified among 326,831 women. The tumors were classified as 400 serous, 83 mucinous, 80 endometroid, 35 clear cell, and 238 unspecified. Compared with never smokers, current smokers had a significantly increased risk for mucinous tumors [HR = 1.85 (95% CI 1.08-3.16)] and those smoking more than 10 cigarettes per day had a doubling in risk [HR = 2.25(95% CI 1.26-4.03)] as did those who had smoked less than 15 pack-years of cigarettes [HR = 2.18 (95% CI 1.07-4.43)]. The results from the EPIC study add further evidence that smoking increases risk of mucinous ovarian cancer and support the notion that the effect of smoking varies according to histological subtype.

  • 22.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chlamydia trachomatis as a risk factor for infertility in women and men, and ovarian tumor development2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Chlamydia trachomatis in women is a risk factor for tubal factor infertility and extra uterine pregnancies, but the impact of a C. trachomatis infection on male fertility is unclear. It is also hypothesized that persistent infection with C. trachomatis, or other microorganisms, might initiate/promote ovarian tumor development. The aims of the thesis were to study whether C. trachomatis serum antibodies in women and men had an impact on infertility diagnoses, semen characteristics, pregnancy rates and pregnancy outcomes; furthermore, to explore associations of C. trachomatis, and Mycoplasma genitalium, plasma antibodies with epithelial ovarian cancer and borderline ovarian tumors, as well as the presence of C. trachomatis bacteria, and other microorganisms, in ovarian tissues.

    Materials and methods: Papers I and II: 244/226 infertile couples were tested for serum C. trachomatis IgG, IgA, IgM and chlamydial Heat Shock Protein 60 (cHSP60) IgG antibodies. C. trachomatis IgG positive couples were also tested for C. trachomatis DNA in a urine sample. The follow-up period was 14-54 months. 244 spontaneously pregnant women were also tested for serum C. trachomatis IgG antibodies. Papers III and IV: Plasma samples from 291 women with epithelial ovarian cancer, borderline ovarian tumors and benign conditions, and plasma samples from 271 healthy controls, were analyzed for C. trachomatis IgG, IgA and cHSP60-1 IgG and M. genitalium IgG antibodies. Ovarian tissues from 186 women with benign ovaries, borderline ovarian tumors and epithelial ovarian cancer, as well as tissues from the contra lateral ovary in 126 women, were analyzed for the presence of C. trachomatis, M. genitalium, Neisseria gonorrhoeae, HPV and the polyoma viruses BKV and JCV with nucleic acid amplification tests.

    Results: Papers I and II: The prevalence of C. trachomatis IgG antibodies was higher among infertile than fertile women, and there were 9 couples with ongoing C. trachomatis infections. In men, C. trachomatis IgG and IgA antibodies were associated with a reduced likelihood to achieve pregnancy for the couple, as well as lower sperm concentration, reduced sperm motility and vitality, increased teratozoospermia index and the occurrence of leukocytes. C. trachomatis IgG and cHSP60 IgG antibodies in infertile women were associated with tubal factor infertility, but not with reduced pregnancy rates or outcomes. Paper III: cHSP60-1 IgG antibodies were associated with ovarian cancer belonging to the postulated type II pathogenetic pathway when plasma samples obtained more than one year prior to diagnosis were analyzed. M. genitalium IgG antibodies were associated with borderline ovarian tumors; however a statistical type 1 error cannot be excluded. Paper IV: None of the microorganisms studied were found in the ovarian tissue samples.

    Conclusions: C. trachomatis IgG and IgA antibodies in the man substantially decreases the chances of the infertile couple to achieve pregnancy, and are associated with subtle negative changes in semen characteristics. C. trachomatis IgG and cHSP60 IgG antibodies in the woman are risk factors for tubal factor infertility. Prospective plasma cHSP60-1 IgG antibodies are associated with type II ovarian carcinomas, but C. trachomatis bacteria, or the other microorganisms studied, could not be detected in benign, borderline or malignant ovarian tissues.

  • 23.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Obstetrik och gynekologi.
    Abramsson, Leif
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Kumlin, U
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Liljeqvist, J A
    Olofsson, J I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Obstetrik och gynekologi.
    Male serum Chlamydia trachomatis IgA and IgG, but not heat shock protein 60 IgG, correlates with negatively affected semen characteristics and lower pregnancy rates in the infertile couple2007In: International Journal of Andrology, ISSN 0105-6263, E-ISSN 1365-2605, Vol. 30, no 2, p. 99-107Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The objective of this study was to evaluate whether serum Chlamydia trachomatis immunoglobulin-A (IgA), IgM and C. trachomatis heat shock protein 60 (CHSP60) IgG are of additional value to C. trachomatis IgG regarding the impact on fecundity in infertile couples, and to relate C. trachomatis serum antibodies to semen characteristics, diagnoses and pregnancy outcome.

    METHODS: A total of 226 infertile couples, previously tested for C. trachomatis IgG, were tested for C. trachomatis IgA, IgM and CHSP60 IgG, and semen samples from all men were analysed.

    RESULTS: Chlamydia trachomatis serum IgA in men (but not in women) correlated with reduced chances of achieving pregnancy [p = 0.021, relative risk (RR) =0.65, 95% confidence interval (CI) 0.42-1.005] and in combination with C. trachomatis IgG the chance was further reduced (p =0.001, RR = 0.35, 95% CI 0.15-0.84). Chlamydia trachomatis serum IgA was also significantly correlated with reduced motility of the spermatozoa (-8.7%, p = 0.023), increased number of dead spermatozoa (+10.5%, p = 0.014) and higher prevalence of leucocytes in semen (+122%, p = 0.005), and in combination with C. trachomatis IgG positivity, there was also a decrease in sperm concentration (-35%, p = 0.033), the number of progressive spermatozoa (-14.8%, p = 0.029) and a rise in the teratozoospermia index (+4.4%, p = 0.010). CHSP60 IgG correlated with reduced motility (-5.6%, p = 0.033), and in the women to tubal factor infertility (p = 0.033), but no correlations of C. trachomatis serum IgM or CHSP60 IgG with pregnancy rates were found.

    CONCLUSIONS: Chlamydia trachomatis serum IgA in the male partner of the infertile couple has an additive value to IgG in predicting pregnancy chances, and serum IgA and IgG are associated with subtle negative changes in semen characteristics.

  • 24.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Olofsson, Jan I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Demonstration of Chlamydia trachomatis IgG antibodies in the male partner of the infertile couple is correlated with a reduced likelihood of achieving pregnancy2004In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 19, no 5, p. 1121-1126Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The objective of this study was to determine the prevalence of Chlamydia trachomatis among both men and women seeking help at an infertility clinic, and to prospectively follow the effect of previous infection on pregnancy rates and pregnancy outcome after a long follow-up period (mean 37 months). 

    METHODS: A total of 244 infertile couples was tested for C. trachomatis IgG antibodies, and IgG(+) couples were also tested for C. trachomatis DNA by PCR in a first-void urine sample. Study parameters were serology, PCR results, clinical diagnoses, treatments, pregnancy rates and pregnancy outcome. As controls, age-matched and spontaneously pregnant women were also tested with serology. 

    RESULTS: The prevalence of IgG antibodies was 24.2, 20.1 and 15.6% among infertile women, infertile men and control women respectively. The prevalence of C. trachomatis DNA was 6.8 and 7.1% among tested women and men respectively. The presence of C. trachomatis IgG antibodies in women was related to tubal factor infertility (TFI) (P = 0.002). Decreased pregnancy rates were seen in couples where the man was IgG(+) (P = 0.005) with no relationship to TFI. Among women who achieved pregnancy, there was no difference in pregnancy outcome between IgG(+) or negative couples. 

    CONCLUSIONS: C. trachomatis IgG antibodies in the man of the infertile couple was related to decreased pregnancy rates and to the presence of IgG antibodies in the woman. There was a high prevalence of asymptomatic persistent infections among infertile couples.

  • 25.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Darelius, Anna
    Sundfeldt, Karin
    Palsson, Mathias
    Strandell, Annika
    Hysterectomy and opportunistic salpingectomy (HOPPSA): study protocol for a register-based randomized controlled trial2019In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 20, article id 10Article in journal (Refereed)
    Abstract [en]

    Background

    There is a great need for a prospective randomized trial to evaluate the risks and benefits of opportunistic salpingectomy. Recently, genetic and morphologic studies have indicated that epithelial ovarian cancer predominantly develops in the Fallopian tubes. Consequently, there is reason to believe that salpingectomy would reduce the risk of ovarian cancer. Studies on reducing the risk of ovarian cancer have compared indicated salpingectomy with no salpingectomy, while studies on surgical safety as well as ovarian function after opportunistic salpingectomy have been small with a short follow-up. No study has reported menopausal symptoms.

    Methods/design

    In this national register-based randomized controlled trial, women <55 years old, planned for a hysterectomy for a benign cause, will be randomized to concomitant salpingectomy or no salpingectomy. The follow-up will be conducted according to already established routines within the register using on-line questionnaires. Primary outcomes have been defined for three different time points: short-term complications up to 8 weeks postoperatively (n = 2800), intermediate-term changes in menopausal symptoms measured by the Menopause Rating Scale at baseline and after 1 year (n = 1670), and long-term epithelial ovarian cancer assessed through national registers after 30 years (n = 5052) (or n = 7001 for high-grade serous cancer). In a sub-study of 75 women, ovarian function will be evaluated through change in anti-Müllerian hormone measured before surgery and after 1 year.

    Discussion

    Hysterectomy for a benign cause is a common surgical procedure and several national societies recommend salpingectomy while performing a benign hysterectomy, despite a lack of scientific evidence for the safety of the procedure. Sweden has unique conditions for clinical trials because of its national quality registers and health registers with excellent quality and near complete coverage. If no additional risks are associated with concomitant salpingectomy, it can be recommended at the time of benign hysterectomy to reduce the risk of epithelial ovarian cancer. If not, the risks and benefits must be balanced. The results of this study will be important for informing women undergoing a benign hysterectomy.

    Trial registration

    ClinicalTrials.gov, NCT03045965. Registered on 8 February 2017

  • 26.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Hermansson, Andrea
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Lalos, Ann
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Social support and ovarian cancer incidence: a Swedish prospective population-based study2018In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 149, no 2, p. 324-328Article in journal (Refereed)
    Abstract [en]

    Objective: Low social support is associated with worse prognosis for epithelial ovarian cancer (EOC) patients. However, few studies have explored the relation between low social support and incidence of EOC. The aim of this prospective nested case-control study was to examine whether self-perceived low social support was associated with the incidence of EOC.

    Methods: The Swedish Cancer Registry was used to identify participants in the Vasterbotten Intervention Programme (VIP) comprising 58,000 women, who later developed EOC. Each case was matched to four cancer free controls. The VIP uses the Social Support questionnaire, a modified version of the validated questionnaire "The Interview Schedule for Social Interaction" (ISSI) measuring quantitative (AVSI) and qualitative (AVAT) aspects of social support.

    Results: The risk of EOC in relation to AVSI and AVAT was similar between the 239 cases and the 941 controls after adjustment for educational level, smoking, BMI, Cambridge Physical Activity Index and age (aOR 0.85, 95% CI 0.72-1.01 and aOR 0.54, 95% CI 0.16-1.81). Lagtime was found to have no impact. A decreased risk of serous ovarian cancer was seen in women with fewer persons available for informal socializing (aOR 0.75, 95% CI 0.59-0.95). Adjusted analyses showed non-significant odds ratios below 1.0 in the vast majority of histotypes.

    Conclusions: A general trend towards a decreased risk of ovarian cancer associated with low AVSI and AVAT was identified. Solely the serous subtype was significantly associated with low scores of AVSI. Prospective pathophysiological and epidemiological studies regarding social support are needed.

  • 27.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Jurstrand, Margaretha
    Olofsson, Jan I.
    Fredlund, Hans
    Mycoplasma genitalium serum antibodies in infertile couples and fertile women2015In: Sexually Transmitted Infections, ISSN 1368-4973, E-ISSN 1472-3263, Vol. 91, no 8, p. 589-591Article in journal (Refereed)
    Abstract [en]

    Objectives: The association between Mycoplasma genitalium (M. genitalium) serum antibodies and infertility in women and men, as well as infertility subtypes, was investigated.

    Methods: Stored serum was obtained from two patient cohorts: infertile couples (239 women and 243 men) attending a gynaecological outpatient clinic between October 1997 and February 2001 and 244 age-matched spontaneously pregnant women. An enzyme immunoassay was used to detect serum immunoglobulin G (IgG) antibodies to M. genitaliumin these samples. Patient's Chlamydia trachomatis seropositivity had been previously determined. Risks were calculated using multivariate logistic regression.

    Results: M. genitalium serum IgG was more common among women of infertile couples (5.4%) than among fertile controls (1.6%) (OR (95%CI) 3.45 (1.10 to 10.75)), adjusting for C. trachomatis IgG (adjusted OR=3.00 (0.95 to 9.47)). Of the women with tubal factor infertility (TFI) 9.1% had M. genitalium IgG compared with 4.6% of women without TFI (OR=2.07 (0.60 to 7.05)); (AOR=1.20 (0.32 to 74.40)). In patients IgG positive to both microorganisms the OR for having TFI was increased (OR=4.86 (1.22 to 19.36)) compared with those positive to C. trachomatis IgG only (AOR=3.14 (1.58 to 6.20)). No associations were found with other infertility diagnoses. Only two men of the infertile couples were M. genitalium IgG positive (0.8%).

    Conclusions: M. genitalium serum IgG was associated with infertility in women, however insignificant after adjustment for C. trachomatis IgG, but not with infertility subtypes within this study. M. genitalium IgG seroprevalence among men was very low and not associated with male factor infertility.

  • 28.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Jurstrand, Margaretha
    Kliniskt forskingscentrum, Örebro universitetssjukhus.
    Møller, Jens K
    Klinisk mikrobiologi, Århus universitetssjukhus, Skejby, Danmark.
    Marklund, Ingrid
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindgren, Peter
    Inst för kvinnors och barns hälsa, obstetrik och gynekologi, Uppsala universitet.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chlamydia trachomatis, Mycoplasma genitalium, Neisseria gonorrhoeae, human papillomavirus, and polyomavirus are not detectable in human tissue with epithelial ovarian cancer, borderline tumor, or benign conditions2010In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 202, no 1, p. 71.e1-71.e6Article in journal (Other academic)
    Abstract [en]

    OBJECTIVE: We sought to analyze the presence of the microorganisms Chlamydia trachomatis, Mycoplasma genitalium, Neisseria gonorrhoeae, human papillomavirus (HPV), and the polyomaviruses BK virus (BKV) and JC virus (JCV) in ovarian tissues of women with ovarian carcinomas, borderline tumors, and benign conditions. STUDY DESIGN: Ovarian tissue, snap-frozen and stored at -80 degrees C, from 186 women with benign conditions, borderline tumors, and epithelial ovarian cancer, as well as tissue from the contralateral ovary of 126 of these women, were analyzed regarding presence of C trachomatis and N gonorrhoeae (transcription mediated amplification), M genitalium (real-time polymerase chain reaction [PCR]), HPV (PCR), and BKV and JCV (PCR). RESULTS: All the tissue samples studied were found negative for the microorganisms analyzed. CONCLUSION: C trachomatis, M genitalium, N gonorrhoeae, HPV, and the polyomaviruses BKV and JCV are not detectable in ovarian tissues either from women with benign conditions and borderline tumors or from women with ovarian cancer.

  • 29.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Jurstrand, Margaretha
    Clinical Research Centre, Örebro University Hospital.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chlamydia trachomatis and Mycoplasma genitalium plasma antibodies in relation to epithelial ovarian tumors2011In: Infectious diseases in obstetrics and gynecology, ISSN 1064-7449, E-ISSN 1098-0997, Vol. 2011, p. 824627-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess associations of Chlamydia trachomatis and Mycoplasma genitalium antibodies with epithelial ovarian tumors.

    METHODS: Plasma samples from 291 women, undergoing surgery due to suspected ovarian pathology, were analyzed with respect to C. trachomatis IgG and IgA, chlamydial Heat Shock Protein 60-1 (cHSP60-1) IgG and M. genitalium IgG antibodies. Women with borderline tumors (n=12), ovarian carcinoma (n=45), or other pelvic malignancies (n=11) were matched to four healthy controls each.

    RESULTS: Overall, there were no associations of antibodies with EOC. However, chlamydial HSP60-1 IgG antibodies were associated with type II ovarian cancer (P=.002) in women with plasma samples obtained >1 year prior to diagnosis (n=7). M. genitalium IgG antibodies were associated with borderline ovarian tumors (P=.01).

    CONCLUSION: Chlamydial HSP60-1 IgG and M. genitalium IgG antibodies are in this study associated with epithelial ovarian tumors in some subsets, which support the hypothesis linking upper-genital tract infections and ovarian tumor development.

  • 30.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jurstrand, Margaretha
    Kliniskt forskningscentrum, Örebro universitetssjukhus.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elgh, Fredrik
    Hälsoakademin, Örebro universitet.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chlamydia trachomatis and Mycoplasma genitalium plasma antibodies in relation to epithelial ovarian tumorsArticle in journal (Other academic)
  • 31.
    Jagarlamudi, Krishna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Lian
    Department of Chemotherapy, Cancer Center, Qilu Hospital, Shandong University, Jinan, China.
    Adhikari, Deepak
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Reddy, Pradeep
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Oocyte-specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 7, p. e6186-Article in journal (Refereed)
    Abstract [en]

    Immature ovarian primordial follicles are essential for maintenance of the reproductive lifespan of female mammals. Recently, it was found that overactivation of the phosphatidylinositol 3-kinase (PI3K) signaling in oocytes of primordial follicles by an oocyte-specific deletion of Pten (phosphatase and tensin homolog deleted on chromosome ten), the gene encoding PI3K negative regulator PTEN, results in premature activation of the entire pool of primordial follicles, indicating that activation of the PI3K pathway in oocytes is important for control of follicular activation. To investigate whether PI3K signaling in oocytes of primary and further developed follicles also plays a role at later stages in follicular development and ovulation, we conditionally deleted the Pten gene from oocytes of primary and further developed follicles by using transgenic mice expressing zona pellucida 3 (Zp3) promoter-mediated Cre recombinase. Our results show that Pten was efficiently deleted from oocytes of primary and further developed follicles, as indicated by the elevated phosphorylation of the major PI3K downstream component Akt. However, follicular development was not altered and oocyte maturation was also normal, which led to normal fertility with unaltered litter size in the mutant mice. Our data indicate that properly controlled PTEN/PI3K-Akt signaling in oocytes is essential for control of the development of primordial follicles whereas overactivation of PI3K signaling in oocytes does not appear to affect the development of growing follicles. This suggests that there is a stage-specific function of PTEN/PI3K signaling in mouse oocytes that controls follicular activation.

  • 32.
    Jonsson, Sarah
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Oda, Husam
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Chlamydia trachomatis, Chlamydial Heat Shock Protein 60 and Anti-Chlamydial Antibodies in Women with Epithelial Ovarian Tumors2018In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 11, no 2, p. 546-551Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Chlamydia trachomatis (C. trachomatis) infection has been suggested to promote epithelial ovarian cancer (EOC) development. This study sought to explore the presence of C. trachomatis DNA and chlamydial heat shock protein 60 (chsp60) in ovarian tissue, as well as anti-chlamydial IgG antibodies in plasma, in relation to subtypes of EOC. METHODS: This cross-sectional cohort consisted of 69 women who underwent surgery due to suspected ovarian pathology. Ovarian tissue and corresponding blood samples were collected at the time of diagnosis. In ovarian tumor tissue, p53, p16, Ki67 and chsp60 were analyzed immunohistochemically, and PCR was used to detect C. trachomatis DNA. Plasma C. trachomatis IgG and cHSP60 IgG were analyzed with a commercial MIF-test and ELISA, respectively. RESULTS: Eight out of 69 women had C. trachomatis DNA in their ovarian tissue, all were invasive ovarian cancer cases (16.7% of invasive EOC). The prevalence of the chsp60 protein, C. trachomatis IgG and cHSP60 IgG in HGSC, compared to other ovarian tumors, was 56.0% vs. 37.2% P = .13, 15.4% vs. 9.3% P = .46 and 63.6% vs. 45.5% P = .33 respectively. None of the markers of C. trachomatis infection were associated with p53, p16 or Ki67. CONCLUSIONS: C. trachomatis was detected in invasive ovarian cancer, supporting a possible role in carcinogenesis of EOC. However, there were no statistically significant associations of chsp60 in ovarian tissue, or plasma anti-chlamydial IgG antibodies, with any of the subtypes of ovarian tumors.

  • 33. Jung, Seungyoun
    et al.
    Allen, Naomi
    Arslan, Alan A.
    Baglietto, Laura
    Barricarte, Aurelio
    Brinton, Louise A.
    Egleston, Brian L.
    Falk, Roni T.
    Fortner, Renée T.
    Helzlsouer, Kathy J.
    Gao, Yutang
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Kaaks, Rudolph
    Krogh, Vittorio
    Merritt, Melissa A.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Onland-Moret, N. Charlotte
    Rinaldi, Sabina
    Schock, Helena
    Shu, Xiao-Ou
    Sluss, Patrick M.
    Staats, Paul N.
    Sacerdote, Carlotta
    Travis, Ruth C.
    Tjønneland, Anne
    Trichopoulou, Antonia
    Tworoger, Shelley S.
    Visvanathan, Kala
    Weiderpass, Elisabete
    Zeleniuch-Jacquotte, Anne
    Dorgan, Joanne F.
    Anti‐Müllerian hormone and risk of ovarian cancer in nine cohorts2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 142, no 2, p. 262-270Article in journal (Refereed)
    Abstract [en]

    Animal and experimental data suggest that anti‐Müllerian hormone (AMH) serves as a marker of ovarian reserve and inhibits the growth of ovarian tumors. However, few epidemiologic studies have examined the association between AMH and ovarian cancer risk. We conducted a nested case‐control study of 302 ovarian cancer cases and 336 matched controls from nine cohorts. Prediagnostic blood samples of premenopausal women were assayed for AMH using a picoAMH enzyme‐linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable‐adjusted conditional logistic regression. AMH concentration was not associated with overall ovarian cancer risk. The multivariable‐adjusted OR (95% CI), comparing the highest to the lowest quartile of AMH, was 0.99 (0.59–1.67) (Ptrend: 0.91). The association did not differ by age at blood draw or oral contraceptive use (all Pheterogeneity: ≥0.26). There also was no evidence for heterogeneity of risk for tumors defined by histologic developmental pathway, stage, and grade, and by age at diagnosis and time between blood draw and diagnosis (all Pheterogeneity: ≥0.39). In conclusion, this analysis of mostly late premenopausal women from nine cohorts does not support the hypothesized inverse association between prediagnostic circulating levels of AMH and risk of ovarian cancer.

  • 34. Jung, Seungyoun
    et al.
    Allen, Naomi
    Arslan, Alan A.
    Baglietto, Laura
    Brinton, Louise A.
    Egleston, Brian L.
    Falk, Roni
    Fortner, Renee T.
    Helzlsouer, Kathy J.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Kaaks, Rudolph
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Merritt, Melissa
    Onland-Moret, Charlotte
    Rinaldi, Sabina
    Sanchez, Maria-Jose
    Sieri, Sabina
    Schock, Helena
    Shu, Xiao-Ou
    Sluss, Patrick M.
    Staats, Paul N.
    Travis, Ruth C.
    Tjonneland, Anne
    Trichopoulou, Antonia
    Tworoger, Shelley
    Visvanathan, Kala
    Krogh, Vittorio
    Weiderpass, Elisabete
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Dorgan, Joanne F.
    Demographic, lifestyle, and other factors in relation to antimullerian hormone levels in mostly late premenopausal women2017In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 107, no 4Article in journal (Refereed)
    Abstract [en]

    Objective: To identify reproductive, lifestyle, hormonal, and other correlates of circulating antimullerian hormone (AMH) concentrations in mostly late premenopausal women. Design: Cross-sectional study. Setting: Not applicable. Patient(s): A total of 671 premenopausal women not known to have cancer. Intervention(s): None. Main Outcome Measure(s): Concentrations of AMH were measured in a single laboratory using the picoAMH ELISA. Multivariable-adjusted median (and interquartile range) AMH concentrations were calculated using quantile regression for several potential correlates. Result(s): Older women had significantly lower AMH concentrations (>= 40 [n = 444] vs. < 35 years [n = 64], multivariable-adjusted median 0.73 ng/mL vs. 2.52 ng/mL). Concentrations of AMH were also significantly lower among women with earlier age at menarche (< 12 [n = 96] vs. >= 14 years [n = 200]: 0.90 ng/mL vs. 1.12 ng/mL) and among current users of oral contraceptives (n = 27) compared with never or former users (n = 468) (0.36 ng/mL vs. 1.15 ng/mL). Race, body mass index, education, height, smoking status, parity, and menstrual cycle phase were not significantly associated with AMH concentrations. There were no significant associations between AMH concentrations and androgen or sex hormone-binding globulin concentrations or with factors related to blood collection (e.g., sample type, time, season, and year of blood collection). Conclusion(s): Among premenopausal women, lower AMH concentrations are associated with older age, a younger age at menarche, and currently using oral contraceptives, suggesting these factors are related to a lower number or decreased secretory activity of ovarian follicles.

  • 35. Kaaks, Rudolf
    et al.
    Fortner, Renée Turzanski
    Hüsing, Anika
    Barrdahl, Myrto
    Hopper, Marika
    Johnson, Theron
    Tjønneland, Anne
    Hansen, Louise
    Overvad, Kim
    Fournier, Agnès
    Boutron-Ruault, Marie-Christine
    Kvaskoff, Marina
    Dossus, Laure
    Johansson, Mattias
    Boeing, Heiner
    Trichopoulou, Antonia
    Benetou, Vassiliki
    La Vecchia, Carlo
    Sieri, Sabina
    Mattiello, Amalia
    Palli, Domenico
    Tumino, Rosario
    Matullo, Giuseppe
    Onland-Moret, N. Charlotte
    Gram, Inger T.
    Weiderpass, Elisabete
    Sánchez, Maria-Jose
    Navarro Sanchez, Carmen
    Duell, Eric J.
    Ardanaz, Eva
    Larranaga, Nerea
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Jirström, Karin
    Nodin, Björn
    Travis, Ruth C.
    Riboli, Elio
    Merritt, Melissa
    Aune, Dagfinn
    Terry, Kathryn
    Cramer, Daniel W.
    Anderson, Karen S.
    Tumor-associated autoantibodies as early detection markers for ovarian cancer?: A prospective evaluation2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 3, p. 515-526Article in journal (Refereed)
    Abstract [en]

    Immuno-proteomic screening has identified several tumor-associated autoantibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53 and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times 6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08-0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10-0.44] for P53 (0.33 [0.11-0.68] for high-grade serous tumors). However, at longer lead-times, the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01-0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited. What's new? Could autoantibodies against tumor antigens provide an early warning system for ovarian cancer? These authors tested how well certain antibodies detected ovarian cancer. They selected four candidate antibodies, to p53, CTAG1A, CTAG2 and NUDT11 proteins, which appear in elevated levels in cancer patients. None of them performed well as a herald of burgeoning cancer. They did not perform any better than the best currently available biomarker, CA125, and as lead times increased past 6 months prediagnosis, the effectiveness diminished. Surprisingly, elevated antibodies appeared in quite a few of the control samples, suggesting they might not be as cancer-specific as expected.

  • 36. Li, K.
    et al.
    Huesing, A.
    Fortner, R. T.
    Tjonneland, A.
    Hansen, L.
    Dossus, L.
    Chang-Claude, J.
    Bergmann, M.
    Steffen, A.
    Bamia, C.
    Trichopoulos, D.
    Trichopoulou, A.
    Palli, D.
    Mattiello, A.
    Agnoli, C.
    Tumino, R.
    Onland-Moret, N. C.
    Peeters, P. H.
    Bueno-de-Mesquita, H. B(as)
    Gram, I. T.
    Weiderpass, E.
    Sanchez-Cantalejo, E.
    Chirlaque, M-D
    Duell, E. J.
    Ardanaz, E.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, E.
    Khaw, K-T
    Travis, R. C.
    Merritt, M. A.
    Gunter, M. J.
    Riboli, E.
    Ferrari, P.
    Terry, K.
    Cramer, D.
    Kaaks, R.
    An epidemiologic risk prediction model for ovarian cancer in Europe: the EPIC study2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, no 7, p. 1257-1265Article in journal (Refereed)
    Abstract [en]

    Background: Ovarian cancer has a high case-fatality ratio, largely due to late diagnosis. Epidemiologic risk prediction models could help identify women at increased risk who may benefit from targeted prevention measures, such as screening or chemopreventive agents. Methods: We built an ovarian cancer risk prediction model with epidemiologic risk factors from 202 206 women in the European Prospective Investigation into Cancer and Nutrition study. Results: Older age at menopause, longer duration of hormone replacement therapy, and higher body mass index were included as increasing ovarian cancer risk, whereas unilateral ovariectomy, longer duration of oral contraceptive use, and higher number of full-term pregnancies were decreasing risk. The discriminatory power (overall concordance index) of this model, as examined with five-fold cross-validation, was 0.64 (95% confidence interval (CI): 0.57, 0.70). The ratio of the expected to observed number of ovarian cancer cases occurring in the first 5 years of follow-up was 0.90 (293 out of 324, 95% CI: 0.81-1.01), in general there was no evidence for miscalibration. Conclusion: Our ovarian cancer risk model containing only epidemiological data showed modest discriminatory power for a Western European population. Future studies should consider adding informative biomarkers to possibly improve the predictive ability of the model.

  • 37.
    Lundin, Eva
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wirgin, Isaac
    Lukanova, Annekatrin
    Afanasyeva, Yelena
    Krogh, Vittorio
    Axelsson, Tomas
    Hemminki, Kari
    Clendenen, Tess V
    Arslan, Alan A
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sieri, Sabina
    Roy, Nirmal
    Koenig, Karen L
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Berrino, Franco
    Toniolo, Paolo
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Försti, Asta
    Muti, Paola
    Lenner, Per
    Shore, Roy E
    Zeleniuch-Jacquotte, Anne
    Selected polymorphisms in sex hormone-related genes, circulating sex hormones and risk of endometrial cancer2012In: Cancer Epidemiology, ISSN 1877-7821, E-ISSN 1877-783X, Vol. 36, no 5, p. 445-452Article in journal (Refereed)
    Abstract [en]

    Background: The role of estrogen and progesterone in the development of endometrial cancer is well documented. Few studies have examined the association of genetic variants in sex hormone-related genes with endometrial cancer risk. Methods: We conducted a case-control study nested within three cohorts to examine the association of endometrial cancer risk with polymorphisms in hormone-related genes among 391 cases (92% postmenopausal at diagnosis) and 712 individually-matched controls. We also examined the association of these polymorphisms with circulating levels of sex hormones and SHBG in a cross-sectional analysis including 596 healthy postmenopausal women at blood donation (controls from this nested case-control study and from a nested case-control study of breast cancer in one of the three cohorts). Results: Adjusting for endometrial cancer risk factors, the A allele of rs4775936 in CYP19 was significantly associated (OR(per allele)=1.22, 95% CI=1.01-1.47, p(trend)=0.04), while the T allele of rs10046 was marginally associated with increased risk of endometrial cancer (OR(per allele)=1.20, 95% CI=0.99-1.45, p(trend)=0.06). PGR rs1042838 was also marginally associated with risk (OR(per allele)=1.25, 95% CI=0.96-1.61, p(trend)=0.09). No significant association was found for the other polymorphisms, i.e. CYP1B1 rs1800440 and rs1056836, UGT1A1 rs8175347, SHBG rs6259 and ESR1 rs2234693. Rs8175347 was significantly associated with postmenopausal levels of estradiol, free estradiol and estrone and rs6259 with SHBG and estradiol. Conclusion: Our findings support an association between genetic variants in CYP19, and possibly PGR, and risk of endometrial cancer.

  • 38. Merritt, Melissa A
    et al.
    Riboli, Elio
    Murphy, Neil
    Kadi, Mai
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Dossus, Laure
    Dartois, Laureen
    Clavel-Chapelon, Françoise
    Fortner, Renée T
    Katzke, Verena A
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Sacerdote, Carlotta
    Panico, Salvatore
    Bueno-de-Mesquita, H Bas
    Peeters, Petra H
    Lund, Eiliv
    Nakamura, Aurelie
    Weiderpass, Elisabete
    Quirós, J Ramón
    Agudo, Antonio
    Molina-Montes, Esther
    Larrañaga, Nerea
    Dorronsoro, Miren
    Cirera, Lluís
    Barricarte, Aurelio
    Olsson, Åsa
    Butt, Salma
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wareham, Nicholas J
    Key, Timothy J
    Brennan, Paul
    Ferrari, Pietro
    Wark, Petra A
    Norat, Teresa
    Cross, Amanda J
    Gunter, Marc J
    Reproductive factors and risk of mortality in the European Prospective Investigation into Cancer and Nutrition: a cohort study2015In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 13, article id 252Article in journal (Refereed)
    Abstract [en]

    Background: Reproductive events are associated with important physiologic changes, yet little is known about how reproductive factors influence long-term health in women. Our objective was to assess the relation of reproductive characteristics with all-cause and cause-specific mortality risk. Methods: The analysis was performed within the European Investigation into Cancer and Nutrition prospective cohort study, which enrolled > 500,000 women and men from 1992 to 2000, who were residing in a given town/geographic area in 10 European countries. The current analysis included 322,972 eligible women aged 25-70 years with 99 % complete follow-up for vital status. We assessed reproductive characteristics reported at the study baseline including parity, age at the first birth, breastfeeding, infertility, oral contraceptive use, age at menarche and menopause, total ovulatory years, and history of oophorectomy/hysterectomy. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for mortality were determined using Cox proportional hazards regression models adjusted for menopausal status, body mass index, physical activity, education level, and smoking status/intensity and duration. Results: During a mean follow-up of 12.9 years, 14,383 deaths occurred. The HR (95 % CI) for risk of all-cause mortality was lower in parous versus nulliparous women (0.80; 0.76-0.84), in women who had ever versus never breastfed (0.92; 0.87-0.97), in ever versus never users of oral contraceptives (among non-smokers; 0.90; 0.86-0.95), and in women reporting a later age at menarche (>= 15 years versus < 12; 0.90; 0.85-0.96; P for trend = 0.038). Conclusions: Childbirth, breastfeeding, oral contraceptive use, and a later age at menarche were associated with better health outcomes. These findings may contribute to the development of improved strategies to promote better long-term health in women.

  • 39. Merritt, Melissa A.
    et al.
    Riboli, Elio
    Weiderpass, Elisabete
    Tsilidis, Konstantinos K.
    Overvad, Kim
    Tjønneland, Anne
    Hansen, Louise
    Dossus, Laure
    Fagherazzi, Guy
    Baglietto, Laura
    Fortner, Renee T.
    Ose, Jennifer
    Steffen, Annika
    Boeing, Heiner
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Lagiou, Pagona
    Masala, Giovanna
    Sieri, Sabina
    Mattiello, Amalia
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-de-Mesquita, H. B(as)
    Onland-Moret, N. Charlotte
    Peeters, Petra H.
    Hjartåker, Anette
    Gram, Inger Torhild
    Ramon Quiros, J.
    Obon-Santacana, Mireia
    Molina-Montes, Esther
    Huerta Castano, Jose Maria
    Ardanaz, Eva
    Chamosa, Saioa
    Sonestedt, Emily
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Travis, Ruth C.
    Rinaldi, Sabina
    Romieu, Isabelle
    Chajes, Veronique
    Gunter, Marc J.
    Dietary fat intake and risk of epithelial ovarian cancer in the European Prospective Investigation into Cancer and Nutrition2014In: Cancer Epidemiology, ISSN 1877-7821, E-ISSN 1877-783X, Vol. 38, no 5, p. 528-537Article in journal (Refereed)
    Abstract [en]

    There are inconsistent and limited data available to assess the relationship between fat intake and risk of epithelial ovarian cancer (EOC). We examined the consumption of total fat, fat sources and fat subtypes in relation to risk of EOC and its major histologic subtypes in the European Prospective Investigation into Cancer and Nutrition which includes incident invasive (n = 1095) and borderline (n = 96) EOC. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In multivariate models, we observed no association with consumption of total fat, animal or plant fat, saturated fat, cholesterol, monounsaturated fat, or fatty fish and risk of invasive EOC. There was, however, an increased risk of invasive EOC in the highest category of intake (Quartile 4 vs. Quartile 1) of polyunsaturated fat (HR = 1.22, 95% CI = 1.02-1.48, P-trend = 0.02). We did not observe heterogeneity in the risk associations in comparisons of serous and endometrioid histologic subtypes. This study does not support an etiological role for total fat intake in relation to EOC risk; however, based on observations of a positive association between intake of polyunsaturated fat and invasive EOC risk in the current and previous studies, this fat subtype warrants further investigation to determine its potential role in EOC development. 

  • 40. Merritt, Melissa A.
    et al.
    Tzoulaki, Ioanna
    Tworoger, Shelley S.
    De Vivo, Immaculata
    Hankinson, Susan E.
    Fernandes, Judy
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Tjonneland, Anne
    Petersen, Kristina E. N.
    Dahm, Christina C.
    Overvad, Kim
    Dossus, Laure
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Fortner, Renee T.
    Kaaks, Rudolf
    Aleksandrova, Krasimira
    Boeing, Heiner
    Trichopoulou, Antonia
    Bamia, Christina
    Trichopoulos, Dimitrios
    Palli, Domenico
    Grioni, Sara
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Bueno-de-Mesquita, H. B. (as)
    Onland-Moret, N. Charlotte
    Peeters, Petra H.
    Gram, Inger T.
    Skeie, Guri
    Ramon Quiros, J.
    Duell, Eric J.
    Sanchez, Maria-Jose
    Salmeron, D.
    Barricarte, Aurelio
    Chamosa, Saioa
    Ericson, Ulrica
    Sonestedt, Emily
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Travis, Ruth C.
    Rinaldi, Sabina
    Romieu, Isabelle
    Patel, Chirag J.
    Riboli, Elio
    Gunter, Marc J.
    Investigation of Dietary Factors and Endometrial Cancer Risk Using a Nutrient-wide Association Study Approach in the EPIC and Nurses' Health Study (NHS) and NHSII2015In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, no 2, p. 466-471Article in journal (Refereed)
    Abstract [en]

    Data on the role of dietary factors in endometrial cancer development are limited and inconsistent. We applied a "nutrient-wide association study" approach to systematically evaluate dietary risk associations for endometrial cancer while controlling for multiple hypothesis tests using the false discovery rate (FDR) and validating the results in an independent cohort. We evaluated endometrial cancer risk associations for dietary intake of 84 foods and nutrients based on dietary questionnaires in three prospective studies, the European Prospective Investigation into Cancer and Nutrition (EPIC; N = 1,303 cases) followed by validation of nine foods/nutrients (FDR <= 0.10) in the Nurses' Health Studies (NHS/NHSII; N = 1,531 cases). Cox regression models were used to estimate HRs and 95% confidence intervals (CI). In multivariate adjusted comparisons of the extreme categories of intake at baseline, coffee was inversely associated with endometrial cancer risk (EPIC, median intake 750 g/day vs. 8.6; HR, 0.81; 95% CI, 0.68-0.97, P-trend = 0.09; NHS/NHSII, median intake 1067 g/day vs. none; HR, 0.82; 95% CI, 0.70-0.96, P-trend = 0.04). Eight other dietary factors that were associated with endometrial cancer risk in the EPIC study (total fat, monounsaturated fat, carbohydrates, phosphorus, butter, yogurt, cheese, and potatoes) were not confirmed in the NHS/NHSII. Our findings suggest that coffee intake may be inversely associated with endometrial cancer risk. Further data are needed to confirm these findings and to examine the mechanisms linking coffee intake to endometrial cancer risk to develop improved prevention strategies. (C)2015 AACR.

  • 41. Merritt, Melissa A.
    et al.
    Tzoulaki, Joanna
    van den Brandt, Piet A.
    Schouten, Leo J.
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Patel, Chirag J.
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    His, Mathilde
    Dartois, Laureen
    Boutron-Ruault, Marie-Christine
    Fortner, Renee T.
    Kaaks, Rudolf
    Aleksandrova, Krasimira
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Bamia, Christina
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Ricceri, Fulvio
    Mattiello, Amalia
    Bueno-de-Mesquita, H. Bas
    Onland-Moret, N. Charlotte
    Peeters, Petra H.
    Skeie, Guri
    Jareid, Mie
    Quiros, J. Ramon
    Obon-Santacana, Mireia
    Sanchez, Maria-Jose
    Chamosa, Saioa
    Huerta, Jose M.
    Barricarte, Aurelio
    Dias, Joana A.
    Sonestedt, Emily
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wareham, Nicholas J.
    Khaw, Kay-Tee
    Travis, Ruth C.
    Ferrari, Pietro
    Riboli, Elio
    Gunter, Marc J.
    Nutrient-wide association study of 57 foods/nutrients and epithelial ovarian cancer in the European Prospective Investigation into Cancer and Nutrition study and the Netherlands Cohort Study2016In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 103, no 1, p. 161-167Article in journal (Refereed)
    Abstract [en]

    Background: Studies of the role of dietary factors in epithelial ovarian cancer (EOC) development have been limited, and no specific dietary factors have been consistently associated with EOC risk.

    Objective: We used a nutrient-wide association study approach to systematically test the association between dietary factors and invasive EOC risk while accounting for multiple hypothesis testing by using the false discovery rate and evaluated the findings in an independent cohort.

    Design: We assessed dietary intake amounts of 28 foods/food groups and 29 nutrients estimated by using dietary questionnaires in the EPIC (European Prospective Investigation into Cancer and Nutrition) study (n = 1095 cases). We selected 4 foods/nutrients that were statistically significantly associated with EOC risk when comparing the extreme quartiles of intake in the EPIC study (false discovery rate = 0.43) and evaluated these factors in the NLCS (Netherlands Cohort Study; n = 383 cases). Cox regression models were used to estimate HRs and 95% CIs.

    Results: None of the 4 dietary factors that were associated with EOC risk in the EPIC study (cholesterol, polyunsaturated and saturated fat, and bananas) were statistically significantly associated with EOC risk in the NLCS; however, in meta-analysis of the EPIC study and the NLCS, we observed a higher risk of EOC with a high than with a low intake of saturated fat (quartile 4 compared with quartile 1; overall HR: 1.21; 95% CI: 1.04, 1.41).

    Conclusion: In the meta-analysis of both studies, there was a higher risk of EOC with a high than with a low intake of saturated fat.

  • 42. Obon-Santacana, Mireia
    et al.
    Lujan-Barroso, Leila
    Travis, Ruth C.
    Freisling, Heinz
    Ferrari, Pietro
    Severi, Gianluca
    Baglietto, Laura
    Boutron-Ruault, Marie-Christine
    Fortner, Renee T.
    Ose, Jennifer
    Boeing, Heiner
    Menendez, Virginia
    Sanchez-Cantalejo, Emilio
    Chamosa, Saioa
    Huerta Castano, Jose Maria
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nick
    Merritt, Melissa A.
    Gunter, Marc J.
    Trichopoulou, Antonia
    Papatesta, Eleni-Maria
    Klinaki, Eleni
    Saieva, Calogero
    Tagliabue, Giovanna
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Bueno-de-Mesquita, H. B.
    Peeters, Petra H.
    Onland-Moret, N. Charlotte
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Weiderpass, Elisabete
    Vesper, Hubert W.
    Riboli, Elio
    Duell, Eric J.
    Acrylamide and Glycidamide Hemoglobin Adducts and Epithelial Ovarian Cancer: A Nested Case-Control Study in Nonsmoking Postmenopausal Women from the EPIC Cohort2016In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 25, no 1, p. 127-134Article in journal (Refereed)
    Abstract [en]

    Background: Acrylamide was classified as “probably carcinogenic to humans (group 2A)” by the International Agency for Research on Cancer. Epithelial ovarian cancer (EOC) is the fourth cause of cancer mortality in women. Five epidemiological studies have evaluated the association between EOC risk and dietary acrylamide intake assessed using food frequency questionnaires, and one nested case–control study evaluated hemoglobin adducts of acrylamide (HbAA) and its metabolite glycidamide (HbGA) and EOC risk; the results of these studies were inconsistent.

    Methods: A nested case–control study in nonsmoking postmenopausal women (334 cases, 417 controls) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Unconditional logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for the association between HbAA, HbGA, HbAA+HbGA, and HbGA/HbAA and EOC and invasive serous EOC risk.

    Results: No overall associations were observed between biomarkers of acrylamide exposure analyzed in quintiles and EOC risk; however, positive associations were observed between some middle quintiles of HbGA and HbAA+HbGA. Elevated but nonstatistically significant ORs for serous EOC were observed for HbGA and HbAA+HbGA (ORQ5vsQ1, 1.91; 95% CI, 0.96–3.81 and ORQ5vsQ1, 1.90; 95% CI, 0.94–3.83, respectively); however, no linear dose–response trends were observed.

    Conclusion: This EPIC nested case–control study failed to observe a clear association between biomarkers of acrylamide exposure and the risk of EOC or invasive serous EOC.

    Impact: It is unlikely that dietary acrylamide exposure increases ovarian cancer risk; however, additional studies with larger sample size should be performed to exclude any possible association with EOC risk.

  • 43. Obon-Santacana, Mireia
    et al.
    Peeters, Petra H. M.
    Freisling, Heinz
    Dossus, Laure
    Clavel-Chapelon, Francoise
    Baglietto, Laura
    Schock, Helena
    Fortner, Renee T.
    Boeing, Heiner
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Menendez, Virginia
    Sanchez, Maria-Jose
    Larranaga, Nerea
    Huerta Castano, Jose Mara
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C.
    Merritt, Melissa A.
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Orfanos, Philippos
    Masala, Giovanna
    Sieri, Sabina
    Tumino, Rosario
    Vineis, Paolo
    Mattiello, Amalia
    Bueno-de-Mesquita, H. B.
    Onland-Moret, N. Charlotte
    Wirfalt, Elisabeth
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Clinical Sciences, Nutrition Epidemiology, Lund University, Malmö, Sweden.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Skeie, Guri
    Gram, Inger T.
    Weiderpass, Elisabete
    Riboli, Elio
    Duell, Eric J.
    Dietary Intake of Acrylamide and Epithelial Ovarian Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort2015In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, no 1, p. 291-297Article in journal (Refereed)
    Abstract [en]

    Acrylamide, classified in 1994 by the International Agency for Research on Cancer (IARC) as "probably carcinogenic" to humans, was discovered in 2002 in some heat-treated, carbohydrate-rich foods. The association between dietary acrylamide intake and epithelial ovarian cancer risk (EOC) has been previously studied in one case-control and three prospective cohort studies which obtained inconsistent results and could not further examine histologic subtypes other than serous EOC. The present study was carried out in the European Prospective Investigation into Cancer and Nutrition (EPIC) subcohort of women (n = 325,006). Multivariate Cox proportional hazards models were used to assess the association between questionnaire-based acrylamide intake and EOC risk. Acrylamide was energy-adjusted using the residual method and was evaluated both as a continuous variable (per 10 mu g/d) and in quintiles; when subgroups by histologic EOC subtypes were analyzed, acrylamide intake was evaluated in quartiles. During a mean follow-up of 11 years, 1,191 incident EOC cases were diagnosed. At baseline, the median acrylamide intake in EPIC was 21.3 mu g/d. No associations and no evidence for a dose-response were observed between energy-adjusted acrylamide intake and EOC risk (HR10 mu(g/d), 1.02; 95% CI, 0.96-1.09; HRQ5vsQ1, 0.97; 95% CI, 0.76-1.23). No differences were seen when invasive EOC subtypes (582 serous, 118 endometrioid, and 79 mucinous tumors) were analyzed separately. This study did not provide evidence that acrylamide intake, based on food intake questionnaires, was associated with risk for EOC in EPIC. Additional studies with more reliable estimates of exposure based on biomarkers may be needed.

  • 44. Obón-Santacana, M.
    et al.
    Kaaks, R.
    Slimani, N.
    Lujan-Barroso, L.
    Freisling, H.
    Ferrari, P.
    Dossus, L.
    Chabbert-Buffet, N.
    Baglietto, L.
    Fortner, R. T.
    Boeing, H.
    Tjønneland, A.
    Olsen, A.
    Overvad, K.
    Menéndez, V.
    Molina-Montes, E.
    Larrañaga, N.
    Chirlaque, M-D
    Ardanaz, E.
    Khaw, K-T
    Wareham, N.
    Travis, R. C.
    Lu, Y.
    Merritt, M. A.
    Trichopoulou, A.
    Benetou, V.
    Trichopoulos, D.
    Saieva, C.
    Sieri, S.
    Tumino, R.
    Sacerdote, C.
    Galasso, R.
    Bueno-de-Mesquita, H. B.
    Wirfalt, E.
    Ericson, U.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Skeie, G.
    Gram, I. T.
    Weiderpass, E.
    Onland-Moret, N. C.
    Riboli, E.
    Duell, E. J.
    Dietary intake of acrylamide and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort2014In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 111, no 5, p. 987-997Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Three prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The objective of this study was to evaluate the association between acrylamide intake and EC risk: for overall EC, for type-I EC, and in never smokers and never users of oral contraceptives (OCs). Smoking is a source of acrylamide, and OC use is a protective factor for EC risk. METHODS: Cox regression was used to estimate hazard ratios (HRs) for the association between acrylamide intake and EC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Acrylamide intake was estimated from the EU acrylamide monitoring database, which was matched with EPIC questionnaire-based food consumption data. Acrylamide intake was energy adjusted using the residual method. RESULTS: No associations were observed between acrylamide intake and overall EC (n = 1382) or type-I EC risk (n = 627). We observed increasing relative risks for type-I EC with increasing acrylamide intake among women who both never smoked and were non-users of OCs (HRQ5vsQ1: 1.97, 95% CI: 1.08-3.62; likelihood ratio test (LRT) P-value: 0.01, n = 203). CONCLUSIONS: Dietary intake of acrylamide was not associated with overall or type-I EC risk; however, positive associations with type I were observed in women who were both non-users of OCs and never smokers.

  • 45. Obón-Santacana, Mireia
    et al.
    Freisling, Heinz
    Peeters, Petra H
    Lujan-Barroso, Leila
    Ferrari, Pietro
    Boutron-Ruault, Marie-Christine
    Mesrine, Sylvie
    Baglietto, Laura
    Turzanski-Fortner, Renee
    Katzke, Verena A
    Boeing, Heiner
    Quirós, J Ramón
    Molina-Portillo, Elena
    Larrañaga, Nerea
    Chirlaque, María-Dolores
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C
    Merritt, Melissa A
    Gunter, Marc J
    Trichopoulou, Antonia
    Lagiou, Pagona
    Naska, Androniki
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Fiano, Valentina
    Galassom, Rocco
    Bueno-de-Mesquita, H B As
    Onland-Moret, N Charlotte
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Weiderpass, Elisabete
    Vesper, Hubert
    Riboli, Elio
    Duell, Eric J
    Acrylamide and glycidamide hemoglobin adduct levels and endometrial cancer risk: a nested case-control study in nonsmoking postmenopausal women from the EPIC cohort2016In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 138, no 5, p. 1129-1138Article in journal (Refereed)
    Abstract [en]

    Acrylamide, classified in 1994 by IARC as "probably carcinogenic to humans," was discovered in 2002 in some heat-treated, carbohydrate-rich foods. Four prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The purpose of this nested case-control study, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, was to evaluate, for the first time, the association between hemoglobin adducts of acrylamide (HbAA) and glycidamide (HbGA) and the risk of developing EC in non-smoking postmenopausal women. Hemoglobin adducts were measured in red blood cells by HPLC/MS/MS. Four exposure variables were evaluated: HbAA, HbGA, their sum (HbAA+HbGA), and their ratio (HbGA/HbAA). The association between hemoglobin adducts and EC was evaluated using unconditional multivariable logistic regression models, and included 383 EC cases (171 were type-I EC), and 385 controls. Exposure variables were analyzed in quintiles based on control distributions. None of the biomarker variables had an effect on overall EC (HRHbAA;Q5vsQ1 : 0.84, 95%CI: 0.49-1.48; HRHbGA;Q5vsQ1 : 0.94, 95%CI: 0.54-1.63) or type-I EC risk. Additionally, none of the subgroups investigated (BMI < 25 vs. ≥25 kg m(-2) , alcohol drinkers vs. never drinkers, oral contraceptive users vs. non-users) demonstrated effect measure modification. Hemoglobin adducts of acrylamide or glycidamide were not associated with EC or type-I EC risk in 768 nonsmoking postmenopausal women from the EPIC cohort.

  • 46. Ose, J.
    et al.
    Fortner, R. T.
    Schock, H.
    Peeters, P. H.
    Onland-Moret, N. C.
    Bueno-de-Mesquita, H. B.
    Weiderpass, E.
    Gram, I. T.
    Overvad, K.
    Tjonneland, A.
    Dossus, L.
    Fournier, A.
    Baglietto, L.
    Trichopoulou, A.
    Benetou, V.
    Trichopoulos, D.
    Boeing, H.
    Masala, G.
    Krogh, V.
    Matiello, A.
    Tumino, R.
    Popovic, M.
    Obon-Santacana, M.
    Larranaga, N.
    Ardanaz, E.
    Sanchez, M-J
    Menendez, V.
    Chirlaque, M-D
    Travis, R. C.
    Khaw, K-T
    Braendstedt, J.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rinaldi, S.
    Kuhn, E.
    Romieu, I.
    Gunter, M. J.
    Merritt, M. A.
    Riboli, E.
    Kaaks, R.
    Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics: results from the EPIC cohort2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, no 1, p. 162-166Article in journal (Refereed)
    Abstract [en]

    Background: Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics. Methods: We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n = 565 cases). Multivariable conditional logistic regression models were used to estimate associations. Results: We observed no association between IGF-I and EOC overall or by tumour characteristics. Conclusions: In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk.

  • 47. Ose, Jennifer
    et al.
    Fortner, Renée T.
    Rinaldi, Sabina
    Schock, Helena
    Overvad, Kim
    Tjonneland, Anne
    Hansen, Louise
    Dossus, Laure
    Fournier, Agnes
    Baglietto, Laura
    Romieu, Isabelle
    Kuhn, Elisabetta
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Masala, Giovanna
    Sieri, Sabina
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Ramon Quiros, Jose
    Obón-Santacana, Mireia
    Larrañaga, Nerea
    Chirlaque, María-Dolores
    Sánchez, María-José
    Barricarte, Aurelio
    Peeters, Petra H.
    Bueno-de-Mesquita, H. B(as)
    Onland-Moret, N. Charlotte
    Brändstedt, Jenny
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Weiderpass, Elisabete
    Gram, Inger T.
    Lund, Eiliv
    Kaw, Kay-Tee
    Travis, Ruth C.
    Merritt, Melissa A.
    Gunther, Marc J.
    Riboli, Elio
    Kaaks, Rudolf
    Endogenous androgens and risk of epithelial invasive ovarian cancer by tumor characteristics in the European Prospective Investigation into Cancer and Nutrition2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 2, p. 399-410Article in journal (Refereed)
    Abstract [en]

    The role of endogenous androgens and sex hormone-binding globulin (SHBG) in ovarian carcinogenesis is poorly understood. Epithelial invasive ovarian cancer (EOC) is a heterogeneous disease and there are no prospective data on endogenous androgens and EOC risk by tumor characteristics (histology, grade, stage) or the dualistic model of ovarian carcinogenesis (i.e. type I vs. type II, leading to less or more aggressive tumors). We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort evaluating androgens and SHBG and invasive EOC risk by tumor characteristics. Female participants who provided a blood sample and were not using exogenous hormones at blood donation were eligible (n = 183,257). A total of 565 eligible women developed EOC; two controls (n = 1,097) were matched per case. We used multivariable conditional logistic regression models. We observed no association between androgens, SHBG and EOC overall. A doubling of androstenedione reduced risk of serous carcinomas by 21% (odds ratio (OR)log2=0.79, 95% confidence interval [CI]=[0.64-0.97]). Moreover, associations differed for low-grade and high-grade carcinomas, with positive associations for low-grade and inverse associations for high-grade carcinomas (e.g. androstenedione: low grade: ORlog2=1.99 [0.98-4.06]; high grade: ORlog2=0.75 [0.61-0.93], p(het)0.01), similar associations were observed for type I/II tumors. This is the first prospective study to evaluate androgens, SHBG and EOC risk by tumor characteristics and type I/II status. Our findings support a possible role of androgens in ovarian carcinogenesis. Additional studies exploring this association are needed. What's new? There appear to be several types of epithelial invasive ovarian cancer (EOC), and hormone-related risk factors are poorly understood. In this study, the authors found that the impact of endogenous androgens on the risk of developing EOC differed depending upon tumor characteristics. Androgen concentrations were positively associated with the risk of low-grade and type-I carcinomas, but the study found an inverse association for high-grade tumors. These findings support a possible role for androgens in ovarian carcinogenesis, and emphasize the need for additional research.

  • 48. Ose, Jennifer
    et al.
    Poole, Elizabeth M.
    Schock, Helena
    Lehtinen, Matti
    Arslan, Alan A.
    Zeleniuch-Jacquotte, Anne
    Visvanathan, Kala
    Helzlsouer, Kathy
    Buring, Julie E.
    Lee, I-Min
    Tjonneland, Anne
    Dossus, Laure
    Trichopoulou, Antonia
    Masala, Giovanna
    Onland-Moret, N. Charlotte
    Weiderpass, Elisabete
    Duell, Eric J.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Travis, Ruth C.
    Rinaldi, Sabina
    Merritt, Melissa A.
    Trabert, Britton
    Wentzensen, Nicolas
    Tworoger, Shelley S.
    Kaaks, Rudolf
    Fortner, Renee T.
    Androgens Are Differentially Associated with Ovarian Cancer Subtypes in the Ovarian Cancer Cohort Consortium2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 14, p. 3951-3960Article in journal (Refereed)
    Abstract [en]

    Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on prediagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case–control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens [testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS)], sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e., histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, ORlog2 = 1.12; 95% confidence interval 1.02–1.24); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors [e.g., testosterone, endometrioid tumors, ORlog2 = 1.40 (1.03–1.91)], but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors [ORlog2 = 0.76 (0.60–0.96)]. Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC.

  • 49. Ose, Jennifer
    et al.
    Schock, Helena
    Poole, Elizabeth M.
    Lehtinen, Matti
    Visvanathan, Kala
    Helzlsouer, Kathy
    Buring, Julie E.
    Lee, I-Min
    Tjonneland, Anne
    Boutron-Ruault, Marie-Christine
    Trichopoulou, Antonia
    Mattiello, Amalia
    Onland-Moret, N. Charlotte
    Weiderpass, Elisabete
    Sanchez, Maria-Jose
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Travis, Ruth C.
    Rinaldi, Sabina
    Merritt, Melissa A.
    Wentzensen, Nicolas
    Tworoger, Shelley S.
    Kaaks, Rudolf
    Fortner, Renee T.
    Pre-diagnosis insulin-like growth factor-I and risk of epithelial invasive ovarian cancer by histological subtypes: A collaborative re-analysis from the Ovarian Cancer Cohort Consortium2017In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 28, no 5, p. 429-435Article in journal (Refereed)
    Abstract [en]

    Biologic evidence suggests that the Insulin-like growth factor (IGF)-family may be involved in the etiology of epithelial invasive ovarian cancer (EOC). However, prospective studies investigating the role of IGF-I in ovarian carcinogenesis have yielded conflicting results. We pooled and harmonized data from 6 case-control studies nested within the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis IGF-I concentrations and subsequent risk of EOC. We evaluated IGF-I concentrations and risk of EOC overall and by tumor subtype (defined by histology, grade, stage) in 1,270 cases and 2,907 matched controls. Multivariable conditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI). Doubling of IGF-I concentration was associated with significantly lower risk of overall EOC [ORlog2 = 0.82; CI 0.72-0.93]. We observed no heterogeneity by tumor characteristics (e.g., histology, p (het) = 0.62), menopausal status at blood collection (p (het) = 0.79), or age at diagnosis (p (het) = 0.60). These results suggest that IGF-I concentrations are inversely associated with EOC risk, independent of histological phenotype. Future prospective research should consider potential mechanisms for this association, including, considering other members of the IGF-family to better characterize the role of IGF-signaling in the etiology of EOC.

  • 50. Ose, Jennifer
    et al.
    Schock, Helena
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    Dossus, Laure
    Clavel-Chapelon, Francoise
    Baglietto, Laura
    Boeing, Heiner
    Trichopolou, Antonia
    Benetou, Vassiliki
    Lagiou, Pagona
    Masala, Giovanna
    Tagliabue, Giovanna
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Bueno-de-Mesquita, H. B(As)
    Peeters, Petra H. M.
    Onland-Moret, N. Charlotte
    Weiderpass, Elisabete
    Gram, Inger T.
    Sanchez, Soledad
    Obon-Santacana, Mireia
    Sanchez-Perez, Maria-Jose
    Larranaga, Nerea
    Huerta Castano, Jose Mara
    Ardanaz, Eva
    Brandstedt, Jenny
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Travis, Ruth C.
    Khaw, Kay-Tee
    Rinaldi, Sabina
    Romieu, Isabelle
    Merritt, Melissa A.
    Gunter, Marc J.
    Riboli, Elio
    Kaaks, Rudolf
    Fortner, Renee T.
    Inflammatory Markers and Risk of Epithelial Ovarian Cancer by Tumor Subtypes: The EPIC Cohort2015In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, no 6, p. 951-961Article in journal (Refereed)
    Abstract [en]

    Background: Evidence suggests an etiologic role for inflammation in ovarian carcinogenesis and heterogeneity between tumor subtypes and anthropometric indices. Prospective studies on circulating inflammatory markers and epithelial invasive ovarian cancer (EOC) have predominantly investigated overall risk; data characterizing risk by tumor characteristics (histology, grade, stage, dualistic model of ovarian carcinogenesis) and anthropometric indices are sparse. Methods: We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate C-reactive protein (CRP), IL6, and EOC risk by tumor characteristics. A total of 754 eligible EOC cases were identified; two controls (n = 1,497) were matched per case. We used multivariable conditional logistic regression to assess associations. Results: CRP and IL6 were not associated with overall EOC risk. However, consistent with prior research, CRP >10 versus CRP <= 1 mg/L was associated with higher overall EOC risk [OR, 1.67 (1.03-2.70)]. We did not observe significant associations or heterogeneity in analyses by tumor characteristics. In analyses stratified by waist circumference, inflammatory markers were associated with higher risk among women with higher waist circumference; no association was observed for women with normal waist circumference [e.g., IL6: waist <= 80: ORlog2, 0.97 (0.81-1.16); waist >88: ORlog2, 1.78 (1.28-2.48), P-heterogeneity <= 0.01]. Conclusions: Our data suggest that high CRP is associated with increased risk of overall EOC, and that IL6 and CRP may be associated with EOC risk among women with higher adiposity. Impact: Our data add to global evidence that ovarian carcinogenesis may be promoted by an inflammatory milieu.

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