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  • 201. Brenner, Darren R
    et al.
    Amos, Christopher I
    Brhane, Yonathan
    Timofeeva, Maria N
    Caporaso, Neil
    Wang, Yufei
    Christiani, David C
    Bickeböller, Heike
    Yang, Ping
    Albanes, Demetrius
    Stevens, Victoria L
    Gapstur, Susan
    McKay, James
    Boffetta, Paolo
    Zaridze, David
    Szeszenia-Dabrowska, Neonilia
    Lissowska, Jolanta
    Rudnai, Peter
    Fabianova, Eleonora
    Mates, Dana
    Bencko, Vladimir
    Foretova, Lenka
    Janout, Vladimir
    Krokan, Hans E
    Skorpen, Frank
    Gabrielsen, Maiken E
    Vatten, Lars
    Njølstad, Inger
    Chen, Chu
    Goodman, Gary
    Lathrop, Mark
    Vooder, Tõnu
    Välk, Kristjan
    Nelis, Mari
    Metspalu, Andres
    Broderick, Peter
    Eisen, Timothy
    Wu, Xifeng
    Zhang, Di
    Chen, Wei
    Spitz, Margaret R
    Wei, Yongyue
    Su, Li
    Xie, Dong
    She, Jun
    Matsuo, Keitaro
    Matsuda, Fumihiko
    Ito, Hidemi
    Risch, Angela
    Heinrich, Joachim
    Rosenberger, Albert
    Muley, Thomas
    Dienemann, Hendrik
    Field, John K
    Raji, Olaide
    Chen, Ying
    Gosney, John
    Liloglou, Triantafillos
    Davies, Michael P A
    Marcus, Michael
    McLaughlin, John
    Orlow, Irene
    Han, Younghun
    Li, Yafang
    Zong, Xuchen
    Johansson, Mattias
    Genetic Epidemiology Division, International Agency for Research on Cancer, Lyon, France.
    Liu, Geoffrey
    Tworoger, Shelley S
    Le Marchand, Loic
    Henderson, Brian E
    Wilkens, Lynne R
    Dai, Juncheng
    Shen, Hongbing
    Houlston, Richard S
    Landi, Maria T
    Brennan, Paul
    Hung, Rayjean J
    Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia2015In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 36, no 11, p. 1314-1326Article in journal (Refereed)
    Abstract [en]

    Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10−8) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10−7) and MTMR2 at 11q21 (rs10501831, P = 3.1×10−6) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10−7) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10−4 for KCNIP4, represented by rs9799795) and AC (P = 2.16×10−4 for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.

  • 202. Brenner, Darren R.
    et al.
    Fanidi, Anouar
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Muller, David C.
    Brennan, Paul
    Manjer, Jonas
    Byrnes, Graham
    Hodge, Allison
    Severi, Gianluca
    Giles, Graham G.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Johansson, Mattias
    Inflammatory Cytokines and Lung Cancer Risk in 3 Prospective Studies2017In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 185, no 2, p. 86-95Article in journal (Refereed)
    Abstract [en]

    To further investigate the role of inflammation in lung carcinogenesis, we evaluated associations between proinflammatory cytokines and lung cancer risk. We conducted a case-control study nested within 3 prospective cohort studies-the Melbourne Collaborative Cohort Study (1990-1994), the Malm Diet and Cancer Study (1991-1996), and the Northern Sweden Health and Disease Study (initiated in 1985)-involving 807 incident lung cancer cases and 807 smoking-matched controls. Conditional logistic regression models adjusting for serum cotinine concentrations were used to estimate odds ratios for lung cancer risk associated with concentrations of interleukin (IL)-1 beta, IL-2, IL-6, IL-8, IL-10, IL-12, interferon., tumor necrosis factor a, and granulocyte-macrophage colony-stimulating factor. We observed a higher lung cancer risk for participants with elevated concentrations of IL-6 and IL-8. These associations seemed to be stronger among former smokers (for fourth quartile vs. first quartile, odds ratio (OR) = 2.70, 95% confidence interval (CI): 1.55, 4.70) and current smokers (OR = 1.99, 95% CI: 1.15, 3.44) for IL-6 and among former smokers (OR = 2.83, 95% CI: 1.18, 6.75) and current smokers (OR = 1.30, 95% CI: 0.69, 2.44) for IL-8. No notable associations were observed among never smokers. Risk associations with IL-6 and IL-8 were observed for blood samples taken close to diagnosis (< 5 years) as well as more than 15 years postdiagnosis.

  • 203. Brenner, Darren R
    et al.
    Yannitsos, Demetra H
    Farris, Megan S
    Johansson, Mattias
    Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France.
    Friedenreich, Christine M
    Leisure-time physical activity and lung cancer risk: a systematic review and meta-analysis2016In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 95, p. 17-27Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: We conducted a systematic review and meta-analysis of the association between recreational physical activity and lung cancer risk to update previous analyses and to examine population subgroups of interest defined by smoking status and histology.

    MATERIALS AND METHODS: We searched the PubMed database for studies up to May 2015. Individual study characteristics were abstracted including study design, number of cases, assessment of recreational physical activity and type and level of adjustment for confounding factors. Combined effect estimates were calculated for the overall associations and across subgroups of interest.

    RESULTS: We identified 28 studies that were eligible for inclusion in the meta-analysis. The overall analysis indicated an inverse association between recreational physical activity and lung cancer risk (Relative Risk (RR), 0.76; 95% Confidence Interval (CI), 0.69-0.85, p-value: <0.001). Similar inverse associations with risk were also noted for all evaluated histological subtypes, including adenocarcinoma (RR, 0.80; 95% CI, 0.72-0.88), squamous (RR, 0.80; 95% CI, 0.71-0.90) and small cell (RR, 0.79; 95% CI, 0.66-0.94). When we examined effects by smoking status, inverse associations between recreational physical activity and lung cancer risk were observed among former (RR, 0.77; 95% CI, 0.69-0.85) and current smokers (RR, 0.77; 95% CI, 0.72-0.83), but not among never smokers (RR, 0.96; 95% CI, 0.79-1.18).

    CONCLUSION: Results from this meta-analysis suggest that regular recreational physical activity may be associated with reduced risk of lung cancer. Only four studies examining never smokers were identified, suggesting the need for additional research in this population.

  • 204. Breugom, A. J.
    et al.
    Bastiaannet, E.
    Boelens, P. G.
    Iversen, L. H.
    Martling, A.
    Johansson, R.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Evans, T.
    Lawton, S.
    O'Brien, K. M.
    Van Eycken, E.
    Janciauskiene, R.
    Liefers, G. J.
    Cervantes, A.
    Lemmens, V. E. P. P.
    van de Velde, C. J. H.
    Adjuvant chemotherapy and relative survival of patients with stage II colon cancer - A EURECCA international comparison between the Netherlands, Denmark, Sweden, England, Ireland, Belgium, and Lithuania2016In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 63, p. 110-117Article in journal (Refereed)
    Abstract [en]

    Background: The aim of the present EURECCA international comparison is to compare adjuvant chemotherapy and relative survival of patients with stage II colon cancer between European countries.

    Methods: Population-based national cohort data (2004-2009) from the Netherlands (NL), Denmark (DK), Sweden (SE), England (ENG), Ireland (IE), and Belgium (BE) were obtained, as well as single-centre data from Lithuania. All surgically treated patients with stage II colon cancer were included. The proportion of patients receiving adjuvant chemotherapy was calculated and compared between countries. Besides, relative survival was calculated and compared between countries.

    Results: Overall, 59,154 patients were included. The proportion of patients receiving adjuvant chemotherapy ranged from 7.1% to 29.0% (p < 0.001). Compared with NL, a better adjusted relative survival was observed in SE (stage II: relative excess risks (RER) 0.53, 95% confidence interval (CI) 0.44-0.64; p < 0.001), and BE (stage II: RER 0.84, 95% CI 0.76-0.92; p < 0.001), and in IE for patients with stage IIA disease (RER 0.80, 95% CI 0.65-0.98; p = 0.03).

    Conclusion: The proportion of patients with stage II colon cancer receiving adjuvant chemotherapy varied largely between seven European countries. No clear linear pattern between adjuvant chemotherapy and adjusted relative survival was observed. Compared with NL, SE and BE showed an improved adjusted relative survival for stage II disease, and IE for patients with stage IIA disease only. Further research into selection criteria for adjuvant chemotherapy could eventually lead to individually tailored, optimal treatment of patients with stage II colon cancer.

  • 205. Bruzzese, Francesca
    et al.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Leone, Alessandra
    Sjöberg, Elin
    Roca, Maria Serena
    Kiflemariam, Sara
    Sjöblom, Tobias
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Egevad, Lars
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Östman, Arne
    Budillon, Alfredo
    Augsten, Martin
    Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF152014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 13, p. 3408-3417Article in journal (Refereed)
    Abstract [en]

    The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGF beta/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. (C)2014 AACR.

  • 206.
    Brynolfsson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Löfstedt, Tommy
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Asklund, Thomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nyholm, Tufve
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Garpebring, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Gray-level invariant Haralick texture features2018In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, p. S279-S280Article in journal (Other academic)
  • 207.
    Brännström, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Bjerregaard, Jon K
    Winbladh, Anders
    Nilbert, Mef
    Revhaug, Arthur
    Wagenius, Gunnar
    Mörner, Malin
    Multidisciplinary team conferences promote treatment according to guidelines in rectal cancer2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 4, p. 447-453Article in journal (Refereed)
    Abstract [en]

    Background. Multidisciplinary team (MDT) conferences have been introduced into standard cancer care, though evidence that it benefits the patient is weak. We used the national Swedish Rectal Cancer Register to evaluate predictors for case discussion at a MDT conference and its impact on treatment.

    Material and methods. Of the 6760 patients diagnosed with rectal cancer in Sweden between 2007 and 2010, 78% were evaluated at a MDT. Factors that influenced whether a patient was discussed at a preoperative MDT conference were evaluated in 4883 patients, and the impact of MDT evaluation on the implementation of preoperative radiotherapy was evaluated in 1043 patients with pT3c-pT4 M0 tumours, and in 1991 patients with pN+ M0 tumours.

    Results. Hospital volume, i.e. the number of rectal cancer surgical procedures performed per year, was the major predictor for MDT evaluation. Patients treated at hospitals with < 29 procedures per year had an odds ratio (OR) for MDT evaluation of 0.15. Age and tumour stage also influenced the chance of MDT evaluation. MDT evaluation significantly predicted the likelihood of being treated with preoperative radiotherapy in patients with pT3c-pT4 M0 tumours (OR 5.06, 95% CI 3.08–8.34), and pN+ M0 (OR 3.55, 95% CI 2.60–4.85), even when corrected for co-morbidity and age.

    Conclusion. Patients with rectal cancer treated at high-volume hospitals are more likely to be discussed at a MDT conference, and that is an independent predictor of the use of adjuvant radiotherapy. These results indirectly support the introduction into clinical practice of discussing all rectal cancer patients at MDT conferences, not least those being treated at low-volume hospitals.

  • 208.
    Brännström, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Gunnarsson, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Risk Factors for Local Recurrence after Emergency Resection for Colon Cancer: Scenario in Sweden2016In: Digestive Surgery, ISSN 0253-4886, E-ISSN 1421-9883, Vol. 33, no 6, p. 503-508Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Patients undergoing emergency resection for colon cancer have a worse outcome both in terms of short-and long-term survival than those having elective surgery. The aim of this population-based study was to determine factors associated with increased risk for local recurrence following emergency resection. Methods: The Stockholm-Gotland Healthcare Region Colon Cancer Register was used to identify all colon cancer patients who had undergone emergency colon resection with curative intent in that region 1997-2007. Patient records were scrutinised to obtain any missing information. The influence of the following factors was assessed: indication for emergency resection; time between admission and surgery; surgery daytime or at night; American Association of Anesthesiologists score; volume of blood lost; and T- and N-stage. Our endpoint was loco-regional recurrence. Results: Apart from stage, perforation as indication for emergency surgery was the only factor that influenced the risk for local recurrence (hazard ratio 1.96; 95% CI 1.12-3.43). Conclusion: In this study, the only factor associated with local recurrence after emergency resection for colon cancer was preoperative perforation. This implies that changes in our current management algorithm would be unlikely to lead to improvement. Efforts should therefore concentrate on reducing the proportion of patients operated on an emergency basis.

  • 209.
    Brännström, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Department of Surgical Sciences, Uppsala University, Uppsala and Department of Surgical Sciences, Karolinska Institutet, Stockholm.
    Jestin, Pia
    Department of Surgical Sciences, Karolinska Institutet, Stockholm and Karlstad Hospital, Karlstad.
    Matthiessen, Peter
    Department of Surgery, Örebro University Hospital, Örebro.
    Gunnarsson, Ulf
    Department of Surgical Sciences, Karolinska Institutet, Stockholm, Sweden.
    Surgeon and hospital-related risk factors in colorectal cancer surgery2011In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 13, no 12, p. 1370-1376Article in journal (Refereed)
    Abstract [en]

    AIM: The aim of this study was to identify surgeon and hospital-related factors in a well-defined population-based cohort; the results of this study could possibly be used to improve outcome in colorectal cancer.

    METHOD: Data from the colonic (1997-2006) and rectal (1995-2006) cancer registers of the Uppsala/Örebro Regional Oncology Centre were used to assess 1697 patients with rectal and 2692 with colonic cancer. Putative risk factors and their impact on long-term survival were evaluated using the Cox proportional hazard model.

    RESULTS: The degree of specialization of the operating surgeon had no significant effect on long-term survival. When comparing the surgeons with the highest degree of specialization, noncolorectal surgeons demonstrated a slightly lower long-term survival for rectal cancer stage I and II (HR, 2.03; 95% CI, 1.05-3.92). Surgeons with a high case-load were not associated with better survival in any analysis model. Regional hospitals had a lower survival rate for rectal cancer stage III surgery (HR, 1.47; 95% CI, 1.08-2.00).

    CONCLUSION: Degree of specialization, surgeon case-load and hospital category could not be identified as important factors when determining outcome in colorectal cancer surgery in this study.

  • 210.
    Brännström, Margareta
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Hägglund, Lena
    Umeå University, Faculty of Medicine, Department of Nursing.
    Fürst, Carl Johan
    Boman, Kurt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Unequal care for dying patients in Sweden: a comparative registry study of deaths from heart disease and cancer2012In: European Journal of Cardiovascular Nursing, ISSN 1474-5151, E-ISSN 1873-1953, Vol. 11, no 4, p. 454-459Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Swedish Palliative Registry is a nationwide quality registry aimed at facilitating improvement in end-of-life care. The goal is for the registry to list and report quality indicators related to care during the last week of life in all cases expected death in Sweden.

    AIM: To examine the quality of care during the last week of life as reported to the registry for patients with heart disease compared to those with cancer.

    METHOD: A retrospective registry study.

    RESULTS: Patients dying of heart disease compared to those dying from cancer had more shortness of breath, fewer drugs prescribed as needed against the usual symptoms and often died alone. Furthermore, they and their close relatives received less information about the imminence of death and bereavement follow-up was less common. The healthcare personnel were less aware of the heart disease patients' symptoms and less often knew about where they wished to die.

    CONCLUSION: Great differences were found in registered end-of-life care suggesting that the care given to patients with heart disease and cancer was unequal even after adjustment for age, sex and setting at the time of death. If our observational findings are confirmed in future studies there is obviously a need for new models for end-of-life management in order to facilitate the provision of equal care to dying patients regardless of diagnosis.

  • 211. Buckland, G
    et al.
    Ros, M M
    Roswall, N
    Bueno-de-Mesquita, H B
    Travier, N
    Tjonneland, A
    Kiemeney, L A
    Sacerdote, C
    Tumino, R
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Gram, I T
    Weiderpass, E
    Skeie, G
    Malm, J
    Ehrnström, R
    Chang-Claude, J
    Mattiello, A
    Agnoli, C
    Peeters, P H
    Boutron-Ruault, M C
    Fagherazzi, G
    Clavel-Chapelon, F
    Nilsson, Lena Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Amiano, P
    Trichopoulou, A
    Oikonomou, E
    Tsiotas, K
    Sánchez, M J
    Overvad, K
    Quirós, J R
    Chirlaque, M D
    Barricarte, A
    Key, T J
    Allen, N E
    Khaw, K T
    Wareham, N
    Riboli, E
    Kaaks, R
    Boeing, H
    Palli, D
    Romieu, I
    Romaguera, D
    Gonzalez, C A
    Adherence to the Mediterranean diet and risk of bladder cancer in the EPIC cohort study2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 10, p. 2504-2511Article in journal (Refereed)
    Abstract [en]

    There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow-up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non-significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 [95% CI 0.69, 1.03]) and risk of aggressive (HR: 0.88 [95% CI 0.61, 1.28]) and non-aggressive tumors (HR: 0.78 [95% CI 0.54, 1.14]). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers.

  • 212. Buckland, G
    et al.
    Travier, N
    Cottet, V
    Gonzalez, CA
    Lujan-Barroso, L
    Agudo, A
    Trichopoulou, A
    Lagiou, P
    Trichopoulos, D
    Peeters, PH
    May, A
    Bueno-de-Mesquita, HB
    Duijnhoven, FJ Bvan
    Key, TJ
    Allen, N
    Khaw, KT
    Wareham, N
    Romieu, I
    McCormack, V
    Boutron-Ruault, M
    Clavel-Chapelon, F
    Panico, S
    Agnoli, C
    Palli, D
    Tumino, R
    Vineis, P
    Amiano, P
    Barricarte, A
    Rodriguez, L
    Sanchez, MJ
    Chirlaque, MD
    Kaaks, R
    Teucher, B
    Boeing, H
    Bergmann, MM
    Overvad, K
    Dahm, CC
    Tjonneland, A
    Olsen, A
    Manjer, J
    Wirfalt, E
    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.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Lund, E
    Hjartaker, A
    Skeie, G
    Vergnaud, AC
    Norat, T
    Romaguera, D
    Riboli, E
    Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 132, no 12, p. 2918-2927Article in journal (Refereed)
    Abstract [en]

    Epidemiological evidence suggests that the Mediterranean diet (MD) could reduce the risk of breast cancer (BC). As evidence from the prospective studies remains scarce and conflicting, we investigated the association between adherence to the MD and risk of BC among 335,062 women recruited from 1992 to 2000, in ten European countries, and followed for 11 years on average. Adherence to the MD was estimated through an adapted relative Mediterranean diet (arMED) score excluding alcohol. Cox proportional hazards regression models were used while adjusting for BC risk factors. A total of 9,009 postmenopausal and 1,216 premenopausal first primary incident invasive BC were identified (5,862 estrogen or progesterone receptor positive [ER+/PR+] and 1,018 estrogen and progesterone receptor negative [ER/PR]). The arMED was inversely associated with the risk of BC overall and in postmenopausal women (high vs. low arMED score; hazard ratio [HR] = 0.94 [95% confidence interval [CI]: 0.88, 1.00] ptrend = 0.048, and HR = 0.93 [95% CI: 0.87, 0.99] ptrend = 0.037, respectively). The association was more pronounced in ER/PR tumors (HR = 0.80 [95% CI: 0.65, 0.99] ptrend = 0.043). The arMED score was not associated with BC in premenopausal women. Our findings show that adherence to a MD excluding alcohol was related to a modest reduced risk of BC in postmenopausal women, and this association was stronger in receptor-negative tumors. The results support the potential scope for BC prevention through dietary modification.

  • 213. Buckland, G.
    et al.
    Travier, N.
    Huerta, J. M.
    Bueno-de-Mesquita, H. B(As)
    Siersema, P. D.
    Skeie, G.
    Weiderpass, E.
    Engeset, D.
    Ericson, U.
    Ohlsson, B.
    Agudo, A.
    Romieu, I.
    Ferrari, P.
    Freisling, H.
    Colorado-Yohar, S.
    Li, K.
    Kaaks, R.
    Pala, V.
    Cross, A. J.
    Riboli, E.
    Trichopoulou, A.
    Lagiou, P.
    Bamia, C.
    Boutron-Ruault, M. C.
    Fagherazzi, G.
    Dartois, L.
    May, A. M.
    Peeters, P. H.
    Panico, S.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC-WHO), France.
    Wallner, Bengt
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palli, D.
    Key, T. J.
    Khaw, K. T.
    Ardanaz, E.
    Overvad, K.
    Tjonneland, A.
    Dorronsoro, M.
    Sanchez, M. J.
    Quiros, J. R.
    Naccarati, A.
    Tumino, R.
    Boeing, H.
    Gonzalez, C. A.
    Healthy lifestyle index and risk of gastric adenocarcinoma in the EPIC cohort study2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 3, p. 598-606Article in journal (Refereed)
    Abstract [en]

    Several modifiable lifestyle factors, including smoking, alcohol, certain dietary factors and weight are independently associated with gastric cancer (GC); however, their combined impact on GC risk is unknown. We constructed a healthy lifestyle index to investigate the joint influence of these behaviors on GC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The analysis included 461,550 participants (662 first incident GC cases) with a mean follow-up of 11.4 years. A healthy lifestyle index was constructed, assigning 1 point for each healthy behavior related to smoking status, alcohol consumption and diet quality (represented by the Mediterranean diet) for assessing overall GC and also body mass index for cardia GC and 0 points otherwise. Risk of GC was calculated using Cox proportional hazards regression models while adjusting for relevant confounders. The highest versus lowest score in the healthy lifestyle index was associated with a significant lower risk of GC, by 51% overall (HR 0.49 95% CI 0.35, 0.70), by 77% for cardia GC (HR 0.23 95% CI 0.08, 0.68) and by 47% for noncardia GC (HR 0.53 (95% CI 0.32, 0.87), p-trends<0.001. Population attributable risk calculations showed that 18.8% of all GC and 62.4% of cardia GC cases could have been prevented if participants in this population had followed the healthy lifestyle behaviors of this index. Adopting several healthy lifestyle behaviors including not smoking, limiting alcohol consumption, eating a healthy diet and maintaining a normal weight is associated with a large decreased risk of GC. What's new? Several modifiable lifestyle factors, including smoking status, alcohol consumption, diet quality and weight, have been independently associated with gastric cancer. Behavioral patterns often cluster, however, lifestyle scores can be used to analyse overlapping risk factors. In this study, the authors used a healthy-lifestyle index to evaluate the combined effects of all of the above factors on the risk of developing gastric cancer (GC). They found that following a healthy lifestyle dramatically decreases the burden of gastric cancer.

  • 214. Budäus, Lars
    et al.
    Bolla, Michel
    Bossi, Alberto
    Cozzarini, Cesare
    Crook, Juanita
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wiegel, Thomas
    Functional Outcomes and Complications Following Radiation Therapy for Prostate Cancer: A Critical Analysis of the Literature2012In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 61, no 1, p. 112-127Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Prostate cancer (PCa) patients have many options within the realms of surgery or radiation therapy (RT). Technical advancements in RT planning and delivery have yielded different approaches, such as external beam, brachytherapy, and newer approaches such as image-guided tomotherapy or volumetric-modulated arc therapy. The selection of the optimal RT treatment for the individual is still a point of discussion, and the debate centres on two important outcomes-namely, cancer control and reduction of side-effects.

    OBJECTIVE: To critically review and summarise the available literature on functional outcomes and rectal sequelae following RT for PCa treatment.

    EVIDENCE ACQUISITION: A review of the literature published between 1999 and 2010 was performed using Medline and Scopus search. Relevant reports were identified using the terms prostate cancer, radiotherapy, functional outcomes, external beam radiation, brachytherapy, IMRT, quality of life, and tomotherapy and were critically reviewed and summarised.

    EVIDENCE SYNTHESIS: Related to nonuniform definition of their assessed functional end points and uneven standards of reporting, only a minority of series retrieved could be selected for analyses. Moreover, patterns of patient selection for different types of RT, inherent differences in the RT modalities, and the presence or absence of hormonal treatment also limit the ability to synthesise results from different publications or perform meta-analyses across the different treatment types. Nonetheless, several studies agree that recent technical improvements in the field of RT planning and delivery enable the administration of higher doses with equal or less toxicity. Regardless of the type of RT, the most frequently considered functional end points in the published analyses are gastrointestinal (GI) complications and rectal bleeding. Established risk factors for acute or late toxicities after RT include advanced age, larger rectal volume, a history of prior abdominal surgery, the concomitant use of androgen deprivation, preexisting diabetes mellitus, haemorrhoids, and inflammatory bowel disease (IBD). Similarly, mild acute irritative urinary symptoms are reported in several studies, whereas total urinary incontinence and other severe urinary symptoms are rare. Pretreatment genitourinary complaints, prior transurethral resection of the prostate (TURP), and the presence of acute genitourinary toxicity are suggested as contributing to long-term urinary morbidity. Erectile dysfunction (ED) is not an immediate side-effect of RT, and the occurrence of spontaneous erections before treatment is the best predictor for preserving erections sufficient for intercourse. In addition, the use of magnetic resonance imaging (MRI) permits a reduction in the dose delivered to vascular structures critical for erectile function.

    CONCLUSIONS: In the future, further improvement in RT planning and delivery will decrease side-effects and permit administration of higher doses. Related to the anatomy of the prostate, these higher doses may favour rectal sparing while not readily sparing the urethra and bladder neck. As a consequence, there may be a future shift from dose-limiting long-term rectal morbidity towards long-term urinary morbidity. In the absence of prospective randomised trials comparing different types of surgical and RT-based treatments in PCa, the introduction of validated tools for reporting functional and clinical outcomes is crucial for evaluating and identifying each individual's best treatment choice.

  • 215. Buunen, Mark
    et al.
    Veldkamp, Ruben
    Hop, Wim C J
    Kuhry, Esther
    Jeekel, Johannes
    Haglind, Eva
    Påhlman, Lars
    Cuesta, Miguel A
    Msika, Simon
    Morino, Mario
    Lacy, Antonio
    Bonjer, Hendrik J
    Lundberg, Owe
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Survival after laparoscopic surgery versus open surgery for colon cancer: long-term outcome of a randomised clinical trial.2009In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 10, no 1, p. 44-52Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Laparoscopic surgery for colon cancer has been proven safe, but debate continues over whether the available long-term survival data justify implementation of laparoscopic techniques in surgery for colon cancer. The aim of the COlon cancer Laparoscopic or Open Resection (COLOR) trial was to compare 3-year disease-free survival and overall survival after laparoscopic and open resection of solitary colon cancer. METHODS: Between March 7, 1997, and March 6, 2003, patients recruited from 29 European hospitals with a solitary cancer of the right or left colon and a body-mass index up to 30 kg/m(2) were randomly assigned to either laparoscopic or open surgery as curative treatment in this non-inferiority randomised trial. Disease-free survival at 3 years after surgery was the primary outcome, with a prespecified non-inferiority boundary at 7% difference between groups. Secondary outcomes were short-term morbidity and mortality, number of positive resection margins, local recurrence, port-site or wound-site recurrence, and blood loss during surgery. Neither patients nor health-care providers were blinded to patient groupings. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00387842. FINDINGS: During the recruitment period, 1248 patients were randomly assigned to either open surgery (n=621) or laparoscopic surgery (n=627). 172 were excluded after randomisation, mainly because of the presence of distant metastases or benign disease, leaving 1076 patients eligible for analysis (542 assigned open surgery and 534 assigned laparoscopic surgery). Median follow-up was 53 months (range 0.03-60). Positive resection margins, number of lymph nodes removed, and morbidity and mortality were similar in both groups. The combined 3-year disease-free survival for all stages was 74.2% (95% CI 70.4-78.0) in the laparoscopic group and 76.2% (72.6-79.8) in the open-surgery group (p=0.70 by log-rank test); the difference in disease-free survival after 3 years was 2.0% (95% CI -3.2 to 7.2). The hazard ratio (HR) for disease-free survival (open vs laparoscopic surgery) was 0.92 (95% CI 0.74-1.15). The combined 3-year overall survival for all stages was 81.8% (78.4-85.1) in the laparoscopic group and 84.2% (81.1-87.3) in the open-surgery group (p=0.45 by log-rank test); the difference in overall survival after 3 years was 2.4% (95% CI -2.1 to 7.0; HR 0.95 [0.74-1.22]). INTERPRETATION: Our trial could not rule out a difference in disease-free survival at 3 years in favour of open colectomy because the upper limit of the 95% CI for the difference just exceeded the predetermined non-inferiority boundary of 7%. However, the difference in disease-free survival between groups was small and, we believe, clinically acceptable, justifying the implementation of laparoscopic surgery into daily practice. Further studies should address whether laparoscopic surgery is superior to open surgery in this setting.

  • 216.
    Bylund, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Jonsson, Joakim
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lundman, Josef
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Brynolfsson, Patrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Garpebring, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nyholm, Tufve
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Löfstedt, Tommy
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Using deep learning to generate synthetic CTs for radiotherapy treatment planning2018In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, p. S283-S283Article in journal (Other academic)
  • 217. Bystrom, Sanna
    et al.
    Fredolini, Claudia
    Edqvist, Per-Henrik
    Nyaiesh, Etienne-Nicholas
    Drobin, Kimi
    Uhlen, Mathias
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Centre for Research and Development, Uppsala University, 751 85 Uppsala, Sweden; Region Gävleborg, Gävle sjukhus, 801 88 Gävle, Sweden.
    Ponten, Fredrik
    Schwenk, Jochen M.
    Affinity Proteomics Exploration of Melanoma Identifies Proteins in Serum with Associations to T-Stage and Recurrence2017In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 10, no 3, p. 385-395Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Blood-based proteomic profiling may aid and expand our understanding of diseases and their different phenotypes. The aim of the presented study was to profile serum samples from patients with malignant melanoma using affinity proteomic assays to describe proteins in the blood stream that are associated to stage or recurrence of melanoma.

    MATERIAL AND METHODS: Multiplexed protein analysis was conducted using antibody suspension bead arrays. A total of 232 antibodies against 132 proteins were selected from (i) a screening with 4595 antibodies and 32 serum samples from melanoma patients and controls, (ii) antibodies used for immunohistochemistry, (iii) protein targets previously related with melanoma. The analysis was performed with 149 serum samples from patients with malignant melanoma. Antibody selectivity was then assessed by Western blot, immunocapture mass spectrometry, and epitope mapping. Lastly, indicative antibodies were applied for IHC analysis of melanoma tissues.

    RESULTS: Serum levels of regucalcin (RGN) and syntaxin 7 (STX7) were found to be lower in patients with both recurring tumors and a high Breslow's thickness (T-stage 3/4) compared to low thickness (T-stage 1/2) without disease recurrence. Serum levels of methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) were instead elevated in sera of T3/4 patients with recurrence. The analysis of tissue sections with S100A6 and MTHFD1L showed positive staining in a majority of patients with melanoma, and S100A6 was significantly associated to T-stage.

    CONCLUSIONS: Our findings provide a starting point to further study RGN, STX7, MTHFD1L and S100A6 in serum to elucidate their involvement in melanoma progression and to assess a possible contribution to support clinical indications.

  • 218. Büchner, Frederike L
    et al.
    Bueno-de-Mesquita, H Bas
    Ros, Martine M
    Overvad, Kim
    Dahm, Christina C
    Hansen, Louise
    Tjønneland, Anne
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Touillaud, Marina
    Kaaks, Rudolf
    Rohrmann, Sabine
    Boeing, Heiner
    Nöthlings, Ute
    Trichopoulou, Antonia
    Zylis, Dimosthenis
    Dilis, Vardis
    Palli, Domenico
    Sieri, Sabina
    Vineis, Paolo
    Tumino, Rosario
    Panico, Salvatore
    Peeters, Petra H M
    van Gils, Carla H
    Lund, Eiliv
    Gram, Inger T
    Braaten, Tonje
    Sánchez, María-José
    Agudo, Antonio
    Larrañaga, Nerea
    Ardanaz, Eva
    Navarro, Carmen
    Argüelles, Marcial V
    Manjer, Jonas
    Wirfält, Elisabet
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Key, Tim J
    Khaw, Kay-Tee
    Wareham, Nick
    Slimani, Nadia
    Vergnaud, Anne-Claire
    Xun, Wei W
    Kiemeney, Lambertus A L M
    Riboli, Elio
    Variety in fruit and vegetable consumption and the risk of lung cancer in the European prospective investigation into cancer and nutrition2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 9, p. 2278-2286Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We investigated whether a varied consumption of vegetables and fruits is associated with lower lung cancer risk in the European Prospective Investigation into Cancer and Nutrition study. METHODS: After a mean follow-up of 8.7 years, 1,613 of 452,187 participants with complete information were diagnosed with lung cancer. Diet diversity scores (DDS) were used to quantify the variety in fruit and vegetable consumption. Multivariable proportional hazards models were used to assess the associations between DDS and lung cancer risk. All models were adjusted for smoking behavior and the total consumption of fruit and vegetables. RESULTS: With increasing variety in vegetable subgroups, risk of lung cancer decreases [hazard ratios (HR), 0.77; 95% confidence interval (CI), 0.64-0.94 highest versus lowest quartile; P trend = 0.02]. This inverse association is restricted to current smokers (HR, 0.73; 95% CI, 0.57-0.93 highest versus lowest quartile; P trend = 0.03). In continuous analyses, in current smokers, lower risks were observed for squamous cell carcinomas with more variety in fruit and vegetable products combined (HR/two products, 0.88; 95% CI, 0.82-0.95), vegetable subgroups (HR/subgroup, 0.88; 95% CI, 0.79-0.97), vegetable products (HR/two products, 0.87; 95% CI, 0.79-0.96), and fruit products (HR/two products, 0.84; 95% CI, 0.72-0.97). CONCLUSION: Variety in vegetable consumption was inversely associated with lung cancer risk among current smokers. Risk of squamous cell carcinomas was reduced with increasing variety in fruit and/or vegetable consumption, which was mainly driven by the effect in current smokers. IMPACT: Independent from quantity of consumption, variety in fruit and vegetable consumption may decrease lung cancer risk.

  • 219. Cai, Feng Feng
    et al.
    Kohler, Corina
    Zhang, Bei
    Chen, Wei Jie
    Barekati, Zeinab
    Garritsen, Henk SP
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Toniolo, Paolo
    Zhang, Jing Jie
    Zhong, Xiao Yan
    Mutations of mitochondrial DNA as potential biomarkers in breast cancer2011In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 31, no 12, p. 4267-4271Article in journal (Refereed)
    Abstract [en]

    Background: Alterations of mitochondrial DNA (mtDNA) have been found in cancer patients, therefore informative mtDNA mutations could serve as biomarkers for the disease.

    Materials and Methods: The two hypervariable regions HVR1 and HVR2 in the D-Loop region were sequenced in ten paired tissue and plasma samples from breast cancer patients.

    Results: MtDNA mutations were found in all patients' samples, suggesting a 100% detection rate. Examining germline mtDNA mutations, a total of 85 mutations in the D-loop region were found; 31 of these mutations were detected in both tissues and matched plasma samples, the other 54 germline mtDNA mutations were found only in the plasma samples. Regarding somatic mtDNA mutations, a total of 42 mutations in the D-loop region were found in breast cancer tissues.

    Conclusion: Somatic mtDNA mutations in the D-loop region were detected in breast cancer tissues but not in the matched plasma samples, suggesting that more sensitive methods will be needed for such detection to be of clinical utility.

  • 220. Caini, Saverio
    et al.
    Masala, Giovanna
    Saieva, Calogero
    Kvaskoff, Marina
    Sacerdote, Carlotta
    Savoye, Isabelle
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Bech, Bodil Hammer
    Overvad, Kim
    Tjonneland, Anne
    Petersen, Kristina E. N.
    Mancini, Francesca Romana
    Boutron-Ruault, Marie-Christine
    Cervenka, Iris
    Kaaks, Rudolf
    Kuehn, Tilman
    Boeing, Heiner
    Floegel, Anna
    Trichopoulou, Antonia
    Valanou, Elisavet
    Kritikou, Maria
    Tagliabue, Giovanna
    Panico, Salvatore
    Tumino, Rosario
    Bueno-de-Mesquita, H. B(as)
    Peeters, Petra H.
    Veierod, Marit B.
    Ghiasvand, Reza
    Lukic, Marko
    Ramon Quiros, Jose
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Salamanca Fernandez, Elena
    Larranaga, Nerea
    Zamora-Ros, Raul
    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.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jirstrom, Karin
    Sonestedt, Emily
    Key, Timothy J.
    Wareham, Nick
    Khaw, Kay-Tee
    Gunter, Marc
    Huybrechts, Inge
    Murphy, Neil
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Palli, Domenico
    Coffee, tea and melanoma risk: findings from the European Prospective Investigation into Cancer and Nutrition2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 10, p. 2246-2255Article in journal (Refereed)
    Abstract [en]

    What's new? Laboratory studies suggest that coffee and tea protect against melanoma, but epidemiological findings are inconsistent. Here the authors studied more than 400,000 participants within the European Prospective Investigation into Cancer and Nutrition (EPIC) and confirmed an inverse association between caffeinated coffee consumption and melanoma risk. No association was found with decaffeinated coffee or tea. Interestingly, drinking coffee only protected men, but not women, from developing the often fatal skin cancer, raising interesting questions about gender-specific hormones or coffee habits influencing this association. In vitro and animal studies suggest that bioactive constituents of coffee and tea may have anticarcinogenic effects against cutaneous melanoma; however, epidemiological evidence is limited to date. We examined the relationships between coffee (total, caffeinated or decaffeinated) and tea consumption and risk of melanoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a multicentre prospective study that enrolled over 500,000 participants aged 25-70 years from ten European countries in 1992-2000. Information on coffee and tea drinking was collected at baseline using validated country-specific dietary questionnaires. We used adjusted Cox proportional hazards regression models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between coffee and tea consumption and melanoma risk. Overall, 2,712 melanoma cases were identified during a median follow-up of 14.9 years among 476,160 study participants. Consumption of caffeinated coffee was inversely associated with melanoma risk among men (HR for highest quartile of consumption vs. non-consumers 0.31, 95% CI 0.14-0.69) but not among women (HR 0.96, 95% CI 0.62-1.47). There were no statistically significant associations between consumption of decaffeinated coffee or tea and the risk of melanoma among both men and women. The consumption of caffeinated coffee was inversely associated with melanoma risk among men in this large cohort study. Further investigations are warranted to confirm our findings and clarify the possible role of caffeine and other coffee compounds in reducing the risk of melanoma.

  • 221. Campa, Daniele
    et al.
    Barrdahl, Myrto
    Gaudet, Mia M.
    Black, Amanda
    Chanock, Stephen J.
    Diver, W. Ryan
    Gapstur, Susan M.
    Haiman, Christopher
    Hankinson, Susan
    Hazra, Aditi
    Henderson, Brian
    Hoover, Robert N.
    Hunter, David J.
    Joshi, Amit D.
    Kraft, Peter
    Le Marchand, Loic
    Lindstrom, Sara
    Willett, Walter
    Travis, Ruth C.
    Amiano, Pilar
    Siddiq, Afshan
    Trichopoulos, Dimitrios
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Tjonneland, Anne
    Weiderpass, Elisabete
    Peeters, Petra H.
    Panico, Salvatore
    Dossus, Laure
    Ziegler, Regina G.
    Canzian, Federico
    Kaaks, Rudolf
    Genetic risk variants associated with in situ breast cancer2015In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, article id 82Article in journal (Refereed)
    Abstract [en]

    Introduction: Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS.

    Methods: To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile.

    Results: We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11-1.38, P = 1.27 x 10(-4)) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99-1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09-1.42, P = 1.07 x 10(-3)). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies.

    Conclusions: Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.

  • 222. Campa, Daniele
    et al.
    Barrdahl, Myrto
    Tsilidis, Konstantinos K
    Severi, Gianluca
    Diver, W Ryan
    Siddiq, Afshan
    Chanock, Stephen
    Hoover, Robert N
    Ziegler, Regina G
    Berg, Christine D
    Buys, Saundra S
    Haiman, Christopher A
    Henderson, Brian E
    Schumacher, Fredrick R
    Le Marchand, Loic
    Flesch-Janys, Dieter
    Lindstroem, Sara
    Hunter, David J
    Hankinson, Susan E
    Willett, Walter C
    Kraft, Peter
    Cox, David G
    Khaw, Kay-Tee
    Tjonneland, Anne
    Dossus, Laure
    Trichopoulos, Dimitrios
    Panico, Salvatore
    van Gils, Carla H
    Weiderpass, Elisabete
    Barricarte, Aurelio
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Gaudet, Mia M
    Giles, Graham
    Southey, Melissa
    Baglietto, Laura
    Chang-Claude, Jenny
    Kaaks, Rudolf
    Canzian, Federico
    A genome-wide "pleiotropy scan'' does not identify new susceptibility loci for estrogen receptor negative breast cancer2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e85955-Article in journal (Refereed)
    Abstract [en]

    Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-). Compared with ER- positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER- negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5x10(-8)) to perform a secondary analysis of an ER- negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER- cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER- GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3 x 10(-4). None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach''.

  • 223. Campa, Daniele
    et al.
    Huesing, Anika
    Dostal, Lucie
    Stein, Angelika
    Drogan, Dagmar
    Boeing, Heiner
    Tjonneland, Anne
    Roswall, Nina
    Ostergaard, Jane Nautrup
    Overvad, Kim
    Rodriguez, Laudina
    Bonet, Catalina
    Sanchez, Maria-Jose
    Larranaga, Nerea
    Maria Huerta, Jose
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nicholas
    Travis, Ruth C.
    Allen, Naomi E.
    Trichopoulou, Antonia
    Zylis, Dimosthenis
    Karapetyan, Tina
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Vineis, Paolo
    Bueno-De-Mesquita, H. Bas
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Jenab, Mazda
    Cox, David
    Siddiq, Afshan
    Kaaks, Rudolf
    Canzian, Federico
    Genetic variability of the forkhead box O3 and prostate cancer risk in the European Prospective Investigation on Cancer2011In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 26, no 4, p. 979-986Article in journal (Refereed)
    Abstract [en]

    Forkhead box O3 (FOXO3) has a wide range of functions: it promotes tumor suppression, cell cycle arrest, repair of damaged DNA, detoxification of reactive oxygen species, apoptosis and plays a pivotal role in promoting longevity. FOXO3 is a key downstream target of the PI3K-Akt pathway in response to cellular stimulation by growth factors or insulin and has been proposed as a bridge between ageing and tumor suppression. Three SNPs in the FOXO3 gene (rs3800231, rs9400239 and rs479744) that have been shown to be strongly and consistently associated with longevity, were examined in relation to PC risk in a case control study of 1571 incident PC cases and 1840 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). There was no statistically significant association between the SNPs and PC risk regardless of the model of inheritance (dominant, codominant and recessive). The associations were not modified by disease aggressiveness, circulating levels of steroid sex hormones, or IGFs or BMI. We conclude that polymorphisms in the FOXO3 gene that are associated with longevity are not major risk factors for PC risk, in this population of Caucasian men.

  • 224. Campa, Daniele
    et al.
    Hüsing, Anika
    Chang-Claude, Jenny
    Dostal, Lucie
    Boeing, Heiner
    Kröger, Janine
    Tjønneland, Anne
    Roswall, Nina
    Overvad, Kim
    Dahm, Christina C
    Rodríguez, Laudina
    Sala, Núria
    Pérez, Maria José Sánchez
    Larrañaga, Nerea
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nick
    Allen, Naomi E
    Travis, Ruth C
    Trichopoulou, Antonia
    Naska, Androniki
    Bamia, Christina
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Sacerdote, Carlotta
    van Kranen, Henk J
    Bas Bueno-de-Mesquita, H
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. International Agency for Research on Cancer, Lyon, France.
    Chajes, Veronique
    Rinaldi, Sabina
    Romieu, Isabelle
    Siddiq, Afshan
    Norat, Teresa
    Riboli, Elio
    Kaaks, Rudolf
    Canzian, Federico
    Genetic variability of the fatty acid synthase pathway is not associated with prostate cancer risk in the European Prospective Investigation on Cancer (EPIC)2011In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 47, no 3, p. 420-427Article in journal (Refereed)
    Abstract [en]

    A western lifestyle, characterised by low rates of energy expenditure and a high-energy diet rich in animal protein, saturated fats and refined carbohydrates, is associated with high incidence of prostate cancer in men. A high-energy nutritional status results in insulin/IGF signalling in cells, which in turn stimulates synthesis of fatty acids. We investigated whether the genetic variability of the genes belonging to the fatty acid synthesis pathway is related to prostate cancer risk in 815 prostate cancer cases and 1266 controls from the European Prospective Investigation on Cancer (EPIC). Using a tagging approach and selecting 252 SNPs in 22 genes, we covered all the common genetic variation of this pathway. None of the SNPs reached statistical significance after adjusting for multiple comparisons. Common SNPs in the fatty acid synthase pathway are not major contributors to prostate cancer risk.

  • 225. Campa, Daniele
    et al.
    Hüsing, Anika
    McKay, James D
    Sinilnikova, Olga
    Vogel, Ulla
    Tjønneland, Anne
    Overvad, Kim
    Stegger, Jakob
    Clavel-Chapelon, Françoise
    Chabbert-Buffet, Nathalie
    Fagherazzi, Guy
    Trichopoulou, Antonia
    Zylis, Dimosthenis
    Oustoglou, Erifili
    Rohrmann, Sabine
    Teucher, Birgit
    Fisher, Eva
    Boeing, Heiner
    Masala, Giovanna
    Krogh, Vittorio
    Sacerdote, Carlotta
    Panico, Salvatore
    Tumino, Rosario
    Onland-Moret, N Charlotte
    van Gils, Carla H
    Bueno-de-Mesquita, H Bas
    Lund, Eiliv
    Chirlaque, María Dolores
    Sala, Núria
    Quirós, José Ramon
    Ardanaz, Eva
    Amiano, Pilar
    Molina-Montes, Esther
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Travis, Ruth C
    Key, Timothy J
    Wareham, Nick
    Khaw, Kay-Tee
    Rinaldi, Sabina
    Slimani, Nadia
    Chajes, Veronique
    Siddiq, Afshan
    Riboli, Elio
    Kaaks, Rudolf
    Canzian, Federico
    The INSIG2 rs7566605 polymorphism is not associated with body mass index and breast cancer risk2010In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 10, p. 563-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The single nucleotide polymorphism rs7566605, located in the promoter of the INSIG2 gene, has been the subject of a strong scientific effort aimed to elucidate its possible association with body mass index (BMI). The first report showing that rs7566605 could be associated with body fatness was a genome-wide association study (GWAS) which used BMI as the primary phenotype. Many follow-up studies sought to validate the association of rs7566605 with various markers of obesity, with several publications reporting inconsistent findings. BMI is considered to be one of the measures of choice to evaluate body fatness and there is evidence that body fatness is related with an increased risk of breast cancer (BC).

    METHODS: we tested in a large-scale association study (3,973 women, including 1,269 invasive BC cases and 2,194 controls), nested within the EPIC cohort, the involvement of rs7566605 as predictor of BMI and BC risk.

    RESULTS AND CONCLUSIONS: In this study we were not able to find any statistically significant association between this SNP and BMI, nor did we find any significant association between the SNP and an increased risk of breast cancer overall and by subgroups of age, or menopausal status.

  • 226. Campa, Daniele
    et al.
    Hüsing, Anika
    Stein, Angelika
    Dostal, Lucie
    Boeing, Heiner
    Pischon, Tobias
    Tjønneland, Anne
    Roswall, Nina
    Overvad, Kim
    Ostergaard, Jane Nautrup
    Rodríguez, Laudina
    Sala, Núria
    Sánchez, Maria-José
    Larrañaga, Nerea
    Huerta, José María
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nicholas
    Travis, Ruth C
    Allen, Naomi E
    Lagiou, Pagona
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Sacerdote, Carlotta
    van Kranen, Henk
    Bueno-de-Mesquita, H Bas
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Romieu, Isabelle
    Jenab, Mazda
    Cox, David G
    Siddiq, Afshan
    Riboli, Elio
    Canzian, Federico
    Kaaks, Rudolf
    Genetic variability of the mTOR pathway and prostate cancer risk in the European prospective investigation on cancer (EPIC)2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, p. e16914-Article in journal (Refereed)
    Abstract [en]

    The mTOR (mammalian target of rapamycin) signal transduction pathway integrates various signals, regulating ribosome biogenesis and protein synthesis as a function of available energy and amino acids, and assuring an appropriate coupling of cellular proliferation with increases in cell size. In addition, recent evidence has pointed to an interplay between the mTOR and p53 pathways. We investigated the genetic variability of 67 key genes in the mTOR pathway and in genes of the p53 pathway which interact with mTOR. We tested the association of 1,084 tagging SNPs with prostate cancer risk in a study of 815 prostate cancer cases and 1,266 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). We chose the SNPs (n = 11) with the strongest association with risk (p<0.01) and sought to replicate their association in an additional series of 838 prostate cancer cases and 943 controls from EPIC. In the joint analysis of first and second phase two SNPs of the PRKCI gene showed an association with risk of prostate cancer (OR(allele) = 0.85, 95% CI 0.78-0.94, p = 1.3×10(-3) for rs546950 and OR(allele) = 0.84, 95% CI 0.76-0.93, p = 5.6×10(-4) for rs4955720). We confirmed this in a meta-analysis using as replication set the data from the second phase of our study jointly with the first phase of the Cancer Genetic Markers of Susceptibility (CGEMS) project. In conclusion, we found an association with prostate cancer risk for two SNPs belonging to PRKCI, a gene which is frequently overexpressed in various neoplasms, including prostate cancer.

  • 227. Campa, Daniele
    et al.
    Kaaks, Rudolf
    Le Marchand, Loic
    Haiman, Christopher A.
    Travis, Ruth C.
    Berg, Christine D.
    Buring, Julie E.
    Chanock, Stephen J.
    Diver, W. Ryan
    Dostal, Lucie
    Fournier, Agnes
    Hankinson, Susan E.
    Henderson, Brian E.
    Hoover, Robert N.
    Isaacs, Claudine
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC), Lyon, France.
    Kolonel, Laurence N.
    Kraft, Peter
    Lee, I-Min
    McCarty, Catherine A.
    Overvad, Kim
    Panico, Salvatore
    Peeters, Petra H. M.
    Riboli, Elio
    Jose Sanchez, Maria
    Schumacher, Fredrick R.
    Skeie, Guri
    Stram, Daniel O.
    Thun, Michael J.
    Trichopoulos, Dimitrios
    Zhang, Shumin
    Ziegler, Regina G.
    Hunter, David J.
    Lindstroem, Sara
    Canzian, Federico
    Interactions Between Genetic Variants and Breast Cancer Risk Factors in the Breast and Prostate Cancer Cohort Consortium2011In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 103, no 16, p. 1252-1263Article in journal (Refereed)
    Abstract [en]

    Background Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer. Methods To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 x 10(-4)) was done. Casecase comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided. Results We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 x 10(-3) -3.96 x 10(-19)). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028). Conclusion This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.

  • 228. Campa, Daniele
    et al.
    Mergarten, Bjoern
    De Vivo, Immaculata
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Severi, Gianluca
    Nieters, Alexandra
    Katzke, Verena A.
    Trichopoulou, Antonia
    Yiannakouris, Nikos
    Trichopoulos, Dimitrios
    Boeing, Heiner
    Ramon Quiros, J.
    Duell, Eric J.
    Molina-Montes, Esther
    Mara Huerta, Jose
    Ardanaz, Eva
    Dorronsoro, Miren
    Khaw, Kay-Tee
    Wareham, Nicholas
    Travis, Ruth C.
    Palli, Domenico
    Pala, Valeria
    Tumino, Rosario
    Naccarati, Alessio
    Panico, Salvatore
    Vineis, Paolo
    Riboli, Elio
    Siddiq, Afshan
    Bueno-de-Mesquita, H. B.
    Peeters, Petra H.
    Nilsson, Peter M.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Karolinska Inst, Dept Med Epidemiol & Biostat.
    Lund, Eiliv
    Jareid, Mie
    Weiderpass, Elisabete
    Duarte-Salles, Talita
    Kong, So Yeon
    Stepien, Magdalena
    Canzian, Federico
    Kaaks, Rudolf
    Leukocyte Telomere Length in Relation to Pancreatic Cancer Risk: A Prospective Study2014In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 23, no 11, p. 2447-2454Article in journal (Refereed)
    Abstract [en]

    Background: Several studies have examined leukocyte telomere length (LTL) as a possible predictor for cancer at various organ sites. The hypothesis originally motivating many of these studies was that shorter telomeres would be associated with an increase in cancer risk; the results of epidemiologic studies have been inconsistent, however, and suggested positive, negative, or null associations. Two studies have addressed the association of LTL in relation to pancreatic cancer risk and the results are contrasting. Methods: We measured LTL in a prospective study of 331 pancreatic cancer cases and 331 controls in the context of the European Prospective Investigation into Cancer and Nutrition (EPIC). Results: We observed that the mean LTL was higher in cases (0.59 +/- 0.20) than in controls (0.57 +/- 0.17), although this difference was not statistically significant (P = 0.07), and a basic logistic regression model showed no association of LTL with pancreas cancer risk. When adjusting for levels of HbA1c and C-peptide, however, there was a weakly positive association between longer LTL and pancreatic cancer risk [OR, 1.13; 95% confidence interval (CI), 1.01-1.27]. Additional analyses by cubic spline regression suggested a possible nonlinear relationship between LTL and pancreatic cancer risk (P = 0.022), with a statistically nonsignificant increase in risk at very low LTL, as well as a significant increase at high LTL. Conclusion: Taken together, the results from our study do not support LTL as a uniform and strong predictor of pancreatic cancer. Impact: The results of this article can provide insights into telomere dynamics and highlight the complex relationship between LTL and pancreatic cancer risk.

  • 229. Canzian, Federico
    et al.
    Cox, David G
    Setiawan, V Wendy
    Stram, Daniel O
    Ziegler, Regina G
    Dossus, Laure
    Beckmann, Lars
    Blanché, Hélène
    Barricarte, Aurelio
    Berg, Christine D
    Bingham, Sheila
    Buring, Julie
    Buys, Saundra S
    Calle, Eugenia E
    Chanock, Stephen J
    Clavel-Chapelon, Françoise
    Delancey, John Oliver L
    Diver, W Ryan
    Dorronsoro, Miren
    Haiman, Christopher A
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hankinson, Susan E
    Hunter, David J
    Hüsing, Anika
    Isaacs, Claudine
    Khaw, Kay-Tee
    Kolonel, Laurence N
    Kraft, Peter
    Le Marchand, Loïc
    Lund, Eiliv
    Overvad, Kim
    Panico, Salvatore
    Peeters, Petra H M
    Pollak, Michael
    Thun, Michael J
    Tjønneland, Anne
    Trichopoulos, Dimitrios
    Tumino, Rosario
    Yeager, Meredith
    Hoover, Robert N
    Riboli, Elio
    Thomas, Gilles
    Henderson, Brian E
    Kaaks, Rudolf
    Feigelson, Heather Spencer
    Comprehensive analysis of common genetic variation in 61 genes related to steroid hormone and insulin-like growth factor-I metabolism and breast cancer risk in the NCI breast and prostate cancer cohort consortium.2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 19, p. 3873-84Article in journal (Refereed)
    Abstract [en]

    There is extensive evidence that increases in blood and tissue concentrations of steroid hormones and of insulin-like growth factor I (IGF-I) are associated with breast cancer risk. However, studies of common variation in genes involved in steroid hormone and IGF-I metabolism have yet to provide convincing evidence that such variants predict breast cancer risk. The Breast and Prostate Cancer Cohort Consortium (BPC3) is a collaboration of large US and European cohorts. We genotyped 1416 tagging single nucleotide polymorphisms (SNPs) in 37 steroid hormone metabolism genes and 24 IGF-I pathway genes in 6292 cases of breast cancer and 8135 controls, mostly Caucasian, postmenopausal women from the BPC3. We also imputed 3921 additional SNPs in the regions of interest. None of the SNPs tested was significantly associated with breast cancer risk, after correction for multiple comparisons. The results remained null when cases and controls were stratified by age at diagnosis/recruitment, advanced or nonadvanced disease, body mass index, with or without in situ cases; or restricted to Caucasians. Among 770 estrogen receptor-negative cases, an SNP located 3' of growth hormone receptor (GHR) was marginally associated with increased risk after correction for multiple testing (P(trend) = 1.5 × 10(-4)). We found no significant overall associations between breast cancer and common germline variation in 61 genes involved in steroid hormone and IGF-I metabolism in this large, comprehensive study. Although previous studies have shown that variations in these genes can influence endogenous hormone levels, the magnitude of the effect of single SNPs does not appear to be sufficient to alter breast cancer risk.

  • 230. Cao, Yin
    et al.
    Lindström, Sara
    Schumacher, Fredrick
    Stevens, Victoria L.
    Albanes, Demetrius
    Berndt, Sonja I.
    Boeing, Heiner
    Bueno-de-Mesquita, H. Bas
    Canzian, Federico
    Chamosa, Saioa
    Chanock, Stephen J.
    Diver, W. Ryan
    Gapstur, Susan M.
    Gaziano, J. Michael
    Giovannucci, Edward L.
    Haiman, Christopher A.
    Henderson, Brian
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer, Lyon, France.
    Le Marchand, Loïc
    Palli, Domenico
    Rosner, Bernard
    Siddiq, Afshan
    Stampfer, Meir
    Stram, Daniel O.
    Tamimi, Rulla
    Travis, Ruth C.
    Trichopoulos, Dimitrios
    Willett, Walter C.
    Yeager, Meredith
    Kraft, Peter
    Hsing, Ann W.
    Pollak, Michael
    Lin, Xihong
    Ma, Jing
    Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 5, article id dju218Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.

    METHODS: Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.

    RESULTS: The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P-trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r(2) = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r(2) = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P-trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P-trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P-trend.corr = .04). Prediagnostic IGF1 (HRhighest (vs lowest quartile) = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% Cl = 0.65 to 1.34) levels were not associated with PCa mortality.

    CONCLUSIONS: The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.

  • 231. Carlberg, Michael
    et al.
    Soderqvist, Fredrik
    Hansson Mild, Kjell
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Hardell, Lennart
    Meningioma patients diagnosed 2007-2009 and the association with use of mobile and cordless phones: a case-control study2013In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 12, no 60Article in journal (Refereed)
    Abstract [en]

    Background: To study the association between use of wireless phones and meningioma. Methods: We performed a case-control study on brain tumour cases of both genders aged 18-75 years and diagnosed during 2007-2009. One population-based control matched on gender and age was used to each case. Here we report on meningioma cases including all available controls. Exposures were assessed by a questionnaire. Unconditional logistic regression analysis was performed. Results: In total 709 meningioma cases and 1,368 control subjects answered the questionnaire. Mobile phone use in total produced odds ratio (OR) = 1.0, 95% confidence interval (CI) = 0.7-1.4 and cordless phone use gave OR = 1.1, 95% CI = 0.8-1.5. The risk increased statistically significant per 100 h of cumulative use and highest OR was found in the fourth quartile (>2,376 hours) of cumulative use for all studied phone types. There was no statistically significant increased risk for ipsilateral mobile or cordless phone use, for meningioma in the temporal lobe or per year of latency. Tumour volume was not related to latency or cumulative use in hours of wireless phones. Conclusions: No conclusive evidence of an association between use of mobile and cordless phones and meningioma was found. An indication of increased risk was seen in the group with highest cumulative use but was not supported by statistically significant increasing risk with latency. Results for even longer latency periods of wireless phone use than in this study are desirable.

  • 232. Carlsson, Sigrid
    et al.
    Drevin, Linda
    Loeb, Stacy
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Franck Lissbrant, Ingela
    Robinson, David
    Johansson, Eva
    Stattin, Pär
    Fransson, Per
    Umeå University, Faculty of Medicine, Department of Nursing.
    Population-based study of long-term functional outcomes after prostate cancer treatment2016In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 117, no 6B, p. E36-E45Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate long-term urinary, sexual and bowel functional outcomes after prostate cancer treatment at a median follow-up of 12 years (IQR 11-13).

    PATIENTS AND METHODS: In this nationwide, population-based study, we identified from the National Prostate Cancer Register, Sweden, 6,003 men diagnosed with localized prostate cancer (clinical local stage T1-2, any Gleason score, prostate specific antigen < 20 ng/mL, NX or N0, MX or M0) between 1997 and 2002 who were ≤70 years at diagnosis. 1,000 prostate cancer-free controls were selected, matched for age and county of residence. Functional outcomes were evaluated with a validated self-reported questionnaire.

    RESULTS: Responses were obtained from 3,937/6,003 cases (66%) and 459/1,000 (46%) controls. Twelve years post diagnosis, at a median age of 75 years, the proportion of cases with adverse symptoms was 87% for erectile dysfunction or sexually inactive, 20% for urinary incontinence and 14% for bowel disturbances. The corresponding proportions for controls were 62%, 6% and 7%, respectively. Men with prostate cancer, except those on surveillance, had an increased risk of erectile dysfunction, compared to control men. Radical prostatectomy was associated with increased risk of urinary incontinence (odds ratio; OR 2.29 [95% CI 1.83-2.86] and radiotherapy increased the risk of bowel dysfunction (OR 2.46 [95% CI 1.73-3.49]) compared to control men. Multi-modal treatment, in particular including androgen deprivation therapy (ADT), was associated with the highest risk of adverse effects; for instance radical prostatectomy followed by radiotherapy and ADT was associated with an OR of 3.74 [95 CI 1.76-7.95] for erectile dysfunction and OR 3.22 [95% CI 1.93-5.37] for urinary incontinence.

    CONCLUSION: The proportion of men who suffer long-term impact on functional outcomes after prostate cancer treatment was substantial.

  • 233. Carlsson, Sigrid
    et al.
    Sandin, Fredrik
    Fall, Katja
    Lambe, Mats
    Adolfsson, Jan
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bill-Axelson, Anna
    Risk of suicide in men with low-risk prostate cancer2013In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no 7, p. 1588-1599Article in journal (Refereed)
    Abstract [en]

    Purpose: Risk of suicide is increased among men with prostate cancer. We investigated this association among men with low-risk cancer, usually detected by prostate specific antigen (PSA)-testing. Patients and Methods: Relative risk (RR) of suicide was calculated by use of Poisson regression analysis within the Prostate Cancer data Base Sweden (PCBaSe) 2.0, a nation-wide, population-based database, comparing 105,736 men diagnosed with prostate cancer between 1997-2009 to 528,658 matched prostate cancer-free men. Results: During the first 6 months after diagnosis, there were 38 suicides among men with prostate cancer; incidence rate 0.73 per 1000 person-years (PY) and 30 suicides in the comparison cohort; 0.11 per 1000 PY, corresponding to a RR of suicide of 6.5 (95% confidence interval (CI) 4.0-10). Risk was highest among men with distant metastases, incidence rate 1.25 per 1000 PY, RR 10 (95% CI 5.1-21) but risk was also increased for men with low-risk tumours, incidence rate difference 0.45 per 1000 PY and RR 5.2 (95% CI 2.3-12) and across categories of socioeconomic status and comorbidity. Eighteen months after diagnosis, risk of suicide had decreased to 0.27 per 1000 PY, RR 1.0 (95% CI 0.68-1.5) for low-risk prostate cancer but remained increased among men with metastases, 0.57 per 1000 PY, RR 1.8 (95% CI 1.1-2.9). Conclusion: Although the increase in absolute risk of suicide was modest, our findings reflect the severe psychological stress that prostate cancer patients may experience after diagnosis. The increased risk of suicide observed in men with prostate cancer, including low-risk, calls for increased awareness.

  • 234. Carreras-Torres, Robert
    et al.
    Haycock, Philip C
    Relton, Caroline L
    Martin, Richard M
    Smith, George Davey
    Kraft, Peter
    Gao, Chi
    Tworoger, Shelley
    Le Marchand, Loïc
    Wilkens, Lynne R
    Park, Sungshim L
    Haiman, Christopher
    Field, John K
    Davies, Michael
    Marcus, Michael
    Liu, Geoffrey
    Caporaso, Neil E
    Christiani, David C
    Wei, Yongyue
    Chen, Chu
    Doherty, Jennifer A
    Severi, Gianluca
    Goodman, Gary E
    Hung, Rayjean J
    Amos, Christopher I
    McKay, James
    Johansson, Mattias
    Section of Genetics, International Agency for Research on Cancer (IARC), Lyon, France.
    Brennan, Paul
    The causal relevance of body mass index in different histological types of lung cancer: a Mendelian randomization study2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 31121Article in journal (Refereed)
    Abstract [en]

    Body mass index (BMI) is inversely associated with lung cancer risk in observational studies, even though it increases the risk of several other cancers, which could indicate confounding by tobacco smoking or reverse causality. We used the two-sample Mendelian randomization (MR) approach to circumvent these limitations of observational epidemiology by constructing a genetic instrument for BMI, based on results from the GIANT consortium, which was evaluated in relation to lung cancer risk using GWAS results on 16,572 lung cancer cases and 21,480 controls. Results were stratified by histological subtype, smoking status and sex. An increase of one standard deviation (SD) in BMI (4.65 Kg/m(2)) raised the risk for lung cancer overall (OR = 1.13; P = 0.10). This was driven by associations with squamous cell (SQ) carcinoma (OR = 1.45; P = 1.2 × 10(-3)) and small cell (SC) carcinoma (OR = 1.81; P = 0.01). An inverse trend was seen for adenocarcinoma (AD) (OR = 0.82; P = 0.06). In stratified analyses, a 1 SD increase in BMI was inversely associated with overall lung cancer in never smokers (OR = 0.50; P = 0.02). These results indicate that higher BMI may increase the risk of certain types of lung cancer, in particular SQ and SC carcinoma.

  • 235. Carreras-Torres, Robert
    et al.
    Johansson, Mattias
    Haycock, Philip C.
    Wade, Kaitlin H.
    Relton, Caroline L.
    Martin, Richard M.
    Smith, George Davey
    Albanes, Demetrius
    Aldrich, Melinda C.
    Andrew, Angeline
    Arnold, Susanne M.
    Bickeböller, Heike
    Bojesen, Stig E.
    Brunnström, Hans
    Manjer, Jonas
    Brüske, Irene
    Caporaso, Neil E.
    Chen, Chu
    Christiani, David C.
    Christian, W. Jay
    Doherty, Jennifer A.
    Duell, Eric J.
    Field, John K.
    Davies, Michael P. A.
    Marcus, Michael W.
    Goodman, Gary E.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Haugen, Aage
    Hong, Yun-Chul
    Kiemeney, Lambertus A.
    van der Heijden, Erik H. F. M.
    Kraft, Peter
    Johansson, Mikael B.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lam, Stephen
    Landi, Maria Teresa
    Lazarus, Philip
    Le Marchand, Loïc
    Liu, Geoffrey
    Melander, Olle
    Park, Sungshim L.
    Rennert, Gad
    Risch, Angela
    Haura, Eric B.
    Scelo, Ghislaine
    Zaridze, David
    Mukeriya, Anush
    Savić, Milan
    Lissowska, Jolanta
    Swiatkowska, Beata
    Janout, Vladimir
    Holcatova, Ivana
    Mates, Dana
    Schabath, Matthew B.
    Shen, Hongbing
    Tardon, Adonina
    Teare, Dawn
    Woll, Penella
    Tsao, Ming-Sound
    Wu, Xifeng
    Yuan, Jian-Min
    Hung, Rayjean J.
    Amos, Christopher I.
    McKay, James
    Brennan, Paul
    Obesity, metabolic factors and risk of different histological types of lung cancer: a Mendelian randomization study2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0177875Article in journal (Refereed)
    Abstract [en]

    Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95% CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m(2)]), but not for adenocarcinoma (OR [95% CI] = 0.93 [0.79-1.08]) (P-heterogeneity = 4.3x10(-3)). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10(-3)), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95% CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95% CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

  • 236. Carstam, Louise
    et al.
    Smits, Anja
    Milos, Peter
    Corell, Alba
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bartek, Jiri, Jr.
    Jakola, Asgeir Store
    Neurosurgical patterns of care for diffuse low-grade gliomas in Sweden between 2005 and 20152019In: Neuro-Oncology Practice, ISSN 2054-2577, Vol. 6, no 2, p. 124-133Article in journal (Refereed)
    Abstract [en]

    Background: In the last decade, increasing evidence has evolved for early and maximal safe resection of diffuse low-grade gliomas (LGGs) regarding survival. However, changes in clinical practice are known to occur slowly and we do not know if the scientific evidence has yet resulted in changes in neurosurgical patterns of care.

    Methods: The Swedish Brain Tumor Registry was used to identify all patients with a first-time histopathological diagnosis of LGG between 2005 and 2015. For analysis of surgical treatment patterns, we subdivided assessed time periods into 2005-2008, 2009-2012, and 2013-2015. Population-based data on patient and disease characteristics, surgical management, and outcomes were extracted.

    Results: A total of 548 patients with diffuse World Health Organization grade II gliomas were identified: 142 diagnosed during 2005-2008, 244 during 2009-2012, and 162 during 2013-2015. Resection as opposed to biopsy was performed in 64.3% during 2005-2008, 74.2% during 2009-2012, and 74.1% during 2013-2015 (P = .08). There was no difference among the 3 periods regarding overall survival (P= .11). However, post hoc analysis of data from the 4 (out of 6) centers that covered all 3 time periods demonstrated a resection rate of 64.3% during 2005-2008, 77.4% during 2009-2012, and 75.4% during 2013-2015 (P = .02) and longer survival of patients diagnosed 2009 and onward (P = .04).

    Conclusion: In this nationwide, population-based study we observed a shift over time in favor of LGG resection. Further, a positive correlation between the more active surgical strategy and longer survival is shown, although no causality can be claimed because of possible confounding factors.

  • 237. Castellsagué, Xavier
    et al.
    Pawlita, Michael
    Roura, Esther
    Margall, Núria
    Waterboer, Tim
    Bosch, F Xavier
    de Sanjosé, Silvia
    Gonzalez, Carlos Alberto
    Dillner, Joakim
    Gram, Inger T
    Tjønneland, Anne
    Munk, Christian
    Pala, Valeria
    Palli, Domenico
    Khaw, Kay-Tee
    Barnabas, Ruanne V
    Overvad, Kim
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Steffen, Annika
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Klinaki, Eleni
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Bueno-de-Mesquita, H Bas
    Peeters, Petra H
    Lund, Eiliv
    Weiderpass, Elisabete
    Quirós, J Ramón
    Sánchez, María-José
    Navarro, Carmen
    Barricarte, Aurelio
    Larrañaga, Nerea
    Ekström, Johanna
    Hortlund, Maria
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wareham, Nick
    Travis, Ruth C
    Rinaldi, Sabina
    Tommasino, Massimo
    Franceschi, Silvia
    Riboli, Elio
    Prospective seroepidemiologic study on the role of Human Papillomavirus and other infections in cervical carcinogenesis: Evidence from the EPIC cohort2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 2, p. 440-452Article in journal (Refereed)
    Abstract [en]

    To evaluate prospectively the association between serological markers of selected infections, including HPV, and risk of developing cervical cancer (CC) and pre-cancer, we performed a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study that included 184 cases of invasive CC (ICC), 425 cases of cervical intraepithelial neoplasia (CIN) grade 3 or carcinoma in situ (CIS), and 1,218 matched control women. At enrollment participants completed lifestyle questionnaires and provided sera. Subjects were followed-up for a median of 9 years. Immunoassays were used to detect serum antibodies to Human Herpes Virus 2 (HHV-2), Chlamydia trachomatis (CT), Chlamydia pneumoniae, L1 proteins of mucosal and cutaneous HPV types, E6/E7 proteins of HPV16/18, as well as to four polyomaviruses. Adjusted odds ratios (OR) (and 95% confidence intervals (CI)) for CIN3/CIS and ICC risk were, respectively: 1.6 (1.2-2.0) and 1.8 (1.1-2.7) for L1 seropositivity to any mucosal HPV type, 1.0 (0.4-2.4) and 7.4 (2.8-19.7) for E6 seropositivity to HPV16/18, 1.3 (0.9-1.9) and 2.3 (1.3-4.1) for CT seropositivity, and 1.4 (1.0-2.0) and 1.5 (0.9-2.6) for HHV-2 seropositivity. The highest OR for ICC was observed for HPV16 E6 seropositivity (OR=10.2 (3.3-31.1)). Increasing number of sexually transmitted infections (STIs) was associated with increasing risk. Non-STIs were not associated with CC risk. In conclusion, this large prospective study confirms the important role of HPV and a possible contribution of CT and HHV-2 in cervical carcinogenesis. It further identifies HPV16 E6 seropositivity as the strongest marker to predict ICC well before disease development.

  • 238. Castro, Felipe A.
    et al.
    Ivansson, Emma L.
    Schmitt, Markus
    Juko-Pecirep, Ivana
    Kjellberg, Lennart
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hildesheim, Allan
    Gyllensten, Ulf B.
    Pawlita, Michael
    Contribution of TMC6 and TMC8 (EVER1 and EVER2) variants to cervical cancer susceptibility2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 2, p. 349-355Article in journal (Refereed)
    Abstract [en]

    Cervical cancer (CxCa) is caused by persistent human papillomavirus (HPV) infection; genetic predisposition is also suspected to play a role. Our study is a targeted candidate gene follow-up based on: (i) strong clinical evidence demonstrating that mutations in the TMC6 and TMC8 (EVER1 and EVER2) genes associate with the HPV-associated disease epidermodysplasia verruciformis (EV) and (ii) recent epidemiological data suggesting a genetic susceptibility conferred by polymorphisms in such genes for skin and CxCa. Clarifying the association of the TMC6/8 genes with risk of CxCa will help in understanding why some HPV-infected women develop persistent infection, cervical lesions and eventually cancer while others do not. Twenty-two single nucleotide polymorphisms (SNPs) harboring the TMC6/8 genes were genotyped in 2,989 cases with cervical intraepithelial neoplasia grade III or invasive CxCa and 2,281 controls from the Swedish population. Association was evaluated in logistic regression models. Two SNPs displayed association with cervical disease: rs2290907 [odds ratio (OR)GGvsAA = 0.6, 95% confidence interval (95% CI): 0.30.9, p = 0.02)] and rs16970849 (ORAGvsGG = 0.8, 95% CI: 0.660.98, p = 0.03). The present data support the involvement of the TMC6/8 region in CxCa susceptibility but further analyses are needed to replicate our findings, fully characterize the region and understand the function of the genetic variants involved.

  • 239. Cazzaniga, Walter
    et al.
    Ventimiglia, Eugenio
    Alfano, Massimo
    Robinson, David
    Lissbrant, Ingela Franck
    Carlsson, Stefan
    Styrke, Johan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Montorsi, Francesco
    Salonia, Andrea
    Stattin, Par
    Mini Review on the Use of Clinical Cancer Registers for Prostate Cancer: The National Prostate Cancer Register (NPCR) of Sweden2019In: FRONTIERS IN MEDICINE, ISSN 2296-858X, Vol. 6, article id 51Article, review/survey (Refereed)
    Abstract [en]

    Given the increasing prevalence of cancer, it is vital to systematically collect data in order to monitor disease trends and quality of cancer care. For this purpose, clinical cancer registries have been developed in some countries. These registers are intended to be used as a basis for quality assurance and quality improvement, but they also constitute a rich resource of real world data for research. The aim of thismini-review was to describe the structure and the organization of the National Prostate Cancer Register (NPCR) with some examples on how data in NPCR have affected prostate cancer care in Sweden.

  • 240. Chajes, V.
    et al.
    Assi, N.
    Biessy, C.
    Ferrari, P.
    Rinaldi, S.
    Slimani, N.
    Lenoir, G. M.
    Baglietto, L.
    His, M.
    Boutron-Ruault, M. C.
    Trichopoulou, A.
    Lagiou, P.
    Katsoulis, M.
    Kaaks, R.
    Kuehn, T.
    Panico, S.
    Pala, V.
    Masala, G.
    Bueno-de-Mesquita, H. B.
    Peeters, P. H.
    van Gils, C.
    Hjartaker, A.
    Olsen, K. Standahl
    Barnung, R. Borgund
    Barricarte, A.
    Redondo-Sanchez, D.
    Menendez, V.
    Amiano, P.
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Key, T.
    Khaw, K. T.
    Merritt, M. A.
    Riboli, E.
    Gunter, M. J.
    Romieu, I.
    A prospective evaluation of plasma phospholipid fatty acids and breast cancer risk in the EPIC study2017In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no 11, p. 2836-2842Article in journal (Refereed)
    Abstract [en]

    Background: Intakes of specific fatty acids have been postulated to impact breast cancer risk but epidemiological data based on dietary questionnaires remain conflicting.

    Materials and methods: We assessed the association between plasma phospholipid fatty acids and breast cancer risk in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition study. Sixty fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 2982 incident breast cancer cases matched to 2982 controls. Conditional logistic regression models were used to estimate relative risk of breast cancer by fatty acid level. The false discovery rate (q values) was computed to control for multiple comparisons. Subgroup analyses were carried out by estrogen receptor (ER) and progesterone receptor expression in the tumours.

    Results: A high level of palmitoleic acid [odds ratio (OR) for the highest quartile compared with the lowest OR (Q4–Q1) 1.37; 95% confidence interval (CI), 1.14–1.64; P for trend = 0.0001, q value = 0.004] as well as a high desaturation index (DI16) (16:1n–7/16:0) [OR (Q4–Q1), 1.28; 95% C, 1.07–1.54; P for trend = 0.002, q value = 0.037], as biomarkers of de novo lipogenesis, were significantly associated with increased risk of breast cancer. Levels of industrial trans-fatty acids were positively associated with ER-negative tumours [OR for the highest tertile compared with the lowest (T3–T1)=2.01; 95% CI, 1.03–3.90; P for trend = 0.047], whereas no association was found for ER-positive tumours (P-heterogeneity =0.01). No significant association was found between n-3 polyunsaturated fatty acids and breast cancer risk, overall or by hormonal receptor.

    Conclusion: These findings suggest that increased de novo lipogenesis, acting through increased synthesis of palmitoleic acid, could be a relevant metabolic pathway for breast tumourigenesis. Dietary trans-fatty acids derived from industrial processes may specifically increase ER-negative breast cancer risk.

  • 241.
    Chand, Damini
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Yamazaki, Yasuo
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Ruuth, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Schönherr, Christina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Martinsson, Tommy
    Gothenburg, Sweden.
    Kogner, Per
    Stockholm, Sweden.
    Attiyeh, Edward F
    Philadelphia, PA 19104, USA .
    Maris, John
    Philadelphia, PA 19104, USA .
    Morozova, Olena
    Vancouver, British Columbia V5Z 4S6, Canada .
    Marra, Marco A
    Vancouver, British Columbia V5Z 4S6, Canada .
    Ohira, Miki
    Chiba 260-8717, Japan.
    Nakagawara, Akira
    Chiba 260-8717, Japan.
    Sandström, Per-Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Palmer, Ruth H
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma2013In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 6, no 2, p. 373-382Article in journal (Refereed)
    Abstract [en]

    Neuroblastoma is a childhood extracranial solid tumor which is associated with a number of genetic changes. Included in these genetic alterations are mutations in the kinase domain of the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK), which have been found in both somatic and familial neuroblastoma. In order to treat patients accordingly required characterisation of these mutations in terms of their response to ALK tyrosine kinase inhibitors (TKIs). Here, we report the identification and characterisation of two novel neuroblastoma ALK mutations (A1099T and 1464STOP) which we have investigated together with several previously reported but uncharacterised ALK mutations (T1087I, D1091N, T1151M, M1166R, F1174I and A1234T). In order to understand the potential role of these ALK mutations in neuroblastoma progression we have employed cell culture based systems together with the model organism Drosophila as a readout for ligand-independent activity. Mutation of ALK at position F1174I generates a gain-of-function receptor capable of activating intracellular targets, such as ERK (extracellular signal regulated kinase) and STAT3 (signal transducer and activator of transcription 3) in a ligand independent manner. Analysis of these previously uncharacterised ALK mutants and comparison with ALK(F1174) mutants suggests that ALK mutations observed in neuroblastoma fall into three classes. These are: (i) gain-of-function ligand independent mutations such as ALK(F1174), (ii) kinase-dead ALK mutants, e.g. ALK(I1250T)(Schonherr et al 2011a) or (iii) ALK mutations which are ligand-dependent in nature. Irrespective of the nature of the observed ALK mutants, in every case the activity of the mutant ALK receptors could be abrogated by the ALK inhibitor crizotinib (PF-02341066, Xalkori), albeit with differing levels of sensitivity.

  • 242. 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.

  • 243. Chen, Hanwei
    et al.
    Jiang, Jinzhao
    Gao, Junling
    Liu, Dan
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Cui, Minyi
    Gong, Nan-Jie
    Feng, Shi-Ting
    Luo, Liangping
    Huang, Bingsheng
    Tumor Volumes Measured From Static and Dynamic F-18-fluoro-2-deoxy-D-glucose Positron Emission Tomography-Computed Tomography Scan: Comparison of Different Methods Using Magnetic Resonance Imaging as the Criterion Standard2014In: Journal of computer assisted tomography, ISSN 0363-8715, E-ISSN 1532-3145, Vol. 38, no 2, p. 209-215Article in journal (Refereed)
    Abstract [en]

    Objective: The objective of this study was to compare the accuracy of calculating the primary tumor volumes using a gradient-based method and fixed threshold methods on the standardized uptake value (SUV) maps and the net influx of FDG (Ki) maps from positron emission tomography-computed tomography (PET-CT) images. Materials and Methods: Newly diagnosed patients with head and neck cancer were recruited, and dynamic PET-CT scan and T2-weighted magnetic resonance imaging were performed. The maps of Ki and SUV were calculated from PET-CT images. The tumor volumes were calculated using a gradient-based method and a fixed threshold method at 40% of maximal SUV or maximal Ki. Four kinds of volumes, VOLKi-Gra (from the Ki maps using the gradient-based method), VOLKi-40% (from the Ki maps using the threshold of 40% maximal Ki), VOLSUV-Gra (from the SUV maps using the gradient-based method), and VOLSUV-40% (from the SUV maps using the threshold of 40% maximal SUV), were acquired and compared with VOLMRI (the volumes acquired on T2-weighted images) using the Pearson correlation, paired t test, and similarity analysis. Results: Eighteen patients were studied, of which 4 had poorly defined tumors (PDT). The positron emission tomography-derived volumes were as follows: VOLSUV-40%, 2.1 to 41.2 cm(3) (mean [SD], 12.3 [10.6]); VOLSUV-Gra, 2.2 to 28.1 cm(3) (mean [SD], 13.2 [8.4]); VOLKi-Gra, 2.4 to 17.0 cm(3) (mean [SD], 9.5 [4.6]); and VOLKi-40%, 2.7 to 20.3 cm(3) (mean [SD], 12.0 [6.0]). The VOLMRI ranged from 2.9 to 18.1 cm(3) (mean [SD], 9.1 [3.9]). The VOLKi-Gra significantly correlated with VOLMRI with the highest correlation coefficient (PDT included, R = 0.673, P = 0.002; PDT excluded, R = 0.841, P < 0.001) and presented no difference from VOLMRI (P = 0.672 or 0.561, respectively, PDT included and excluded). The difference between VOLKi-Gra and VOLMRI was also the smallest. Conclusions: The tumor volumes delineated on the Ki maps using the gradient-based method are more accurate than those on the SUV maps and using the fixed threshold methods.

  • 244. Chen, M-J
    et al.
    Wu, Wendy Yi-Ying
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
    Yen, A. M-F
    Fann, J. C-Y
    Chen, S. L-S
    Chiu, S. Y-H
    Chen, H-H
    Chiou, S-T
    Body mass index and breast cancer: analysis of a nation-wide population-based prospective cohort study on 1 393 985 Taiwanese women2016In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, no 3, p. 524-530Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Asian women have a younger age at onset of breast cancer and a lower body mass index (BMI) than Western women. The link between obesity and risk of breast cancer in Asian women is still elusive. We aimed to investigate the effect of BMI on the risk of incident breast cancer in Taiwanese women.

    METHODS: A total of 1 393 985 women who had been cancer-free before recruitment and attended a nation-wide Taiwanese breast cancer-screening program between 1999 and 2009 were enrolled using a prospective cohort study. Obesity and other relevant variables (such as menopause status and other biochemical markers) were collected through in-person interviews, anthropometric measurements and blood samples at first screen. Incident breast cancers during follow-up were ascertained through the linkage of the cohort with the National Cancer Registry and the National Death Certification System.

    RESULTS: A total of 6969 and 7039 incident breast cancer cases were identified among women enrolled before and after menopause, respectively. Compared with a BMI range of 18.5-23.9 kgm(-2), the incremental level of BMI in the enrolled women before menopause revealed a lack of statistically significant association with the risk of incident breast cancer (adjusted hazard ratio = 0.94, 0.98, 1.02, 1.01 and 0.82 for BMI < 18.5, 24-26.9, 27-29.9, 30-34.9 and >= 35, respectively), but the incremental level of BMI in the enrolled women after menopause led to a statistically significant incremental increase in the risk of breast cancer (adjusted hazard ratio = 0.78, 1.19, 1.31, 1.53 and 1.65 for BMI < 18.5, 24-26.9, 27-29.9, 30-34.9 and >= 35, respectively) after adjusting for other explanatory risk factors.

    CONCLUSION: Obesity acts mainly as an influential promoter of the development of late-onset breast cancer after menopause in Taiwanese women.

  • 245. Chen, Tianhui
    et al.
    Surcel, Helja-Marja
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kaasila, Marjo
    Lakso, Hans-Ake
    Schock, Helena
    Kaaks, Rudolf
    Koskela, Pentti
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Pukkala, Eero
    Zeleniuch-Jacquotte, Anne
    Toniolo, Paolo
    Lehtinen, Matti
    Lukanova, Annekatrin
    Circulating sex steroids during pregnancy and maternal risk of non-epithelial ovarian cancer2011In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, no 2, p. 324-336Article in journal (Refereed)
    Abstract [en]

    This is the first prospective study providing initial evidence that elevated androgens play a role in the pathogenesis of SCST. Impact: Our study may note a particular need for larger confirmatory investigations on sex steroids and NEOC. Cancer Epidemiol Biomarkers Prev; 20(2); 324-36. ©2010 AACR.

  • 246. Chinot, O.
    et al.
    Cloughesy, T.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Saran, F.
    Mason, W.
    Nishikawa, R.
    Hilton, M.
    Abrey, L.
    Wick, W.
    Efficacy and safety of bevacizumab (By) plus standard combination temozolomide (T) and radiotherapy (RT) in newly diagnosed glioblastoma: final results from AVAglio2013In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no Supplement 2, p. S774-S775, Meeting Abstract: 3301AArticle in journal (Other academic)
  • 247. Chinot, Olivier
    et al.
    Garcia, Josep
    Romain, Sylvie
    Revil, Cedric
    Cloughesy, Timothy
    Mason, Warren
    Nishikawa, Ryo
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm, Stockholm, Sweden.
    Saran, Frank
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana M.
    Brandes, Alba A.
    Kerloeguen, Yannick
    Mancao, Christoph
    Ouafik, L'Houcine
    Abrey, Lauren
    Wick, Wolfgang
    Tabouret, Emeline
    BASELINE PLASMA MATRIX METALLOPROTEINASE 9 (MMP9) PREDICTS OVERALL SURVIVAL (OS) BENEFIT FROM BEVACIZUMAB INDEPENDENTLY OF MOLECULAR SUBTYPES IN NEWLY DIAGNOSED GLIOBLASTOMA: RETROSPECTIVE ANALYSIS OF AVAglio2016In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, p. 5-5Article in journal (Refereed)
  • 248. Chinot, Olivier L.
    et al.
    Nishikawa, Ryo
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm Gotland, Stockholm, Sweden.
    Saran, Frank
    Cloughesy, Timothy
    Garcia, Josep
    Revil, Cedric
    Abrey, Lauren
    Wick, Wolfgang
    Upfront bevacizumab may extend survival for glioblastoma patients who do not receive second-line therapy: an exploratory analysis of AVAglio2016In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, no 9, p. 1313-1318Article in journal (Refereed)
    Abstract [en]

    Background: In this post-hoc, exploratory analysis, we examined outcomes for patients enrolled in the AVAglio trial of front-line bevacizumab or placebo plus radiotherapy/temozolomide who received only a single line of therapy. Methods: Patients with newly diagnosed glioblastoma received protocol-defined treatment until progressive disease (PD). Co-primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). After confirmed PD, patients were treated at the investigators' discretion. PFS/OS were assessed in patients with a PFS event who did not receive post-PD therapy (Group 1) and patients with a PFS event who received post-PD therapy plus patients who did not have a PFS event at the final data cutoff (Group 2). Kaplan-Meier methodology was used. A multivariate Cox proportional hazards model for known prognostic variables was generated. Results: Baseline characteristics were balanced. In patients with a PFS event who did not receive post-PD therapy (Group 1; n = 225 [24.4% of the intent-to-treat population]), the addition of bevacizumab to radiotherapy/temozolomide resulted in a 3.6-month extension in both median PFS (hazard ratio [HR]: 0.62, P =.0016) and median OS (HR: 0.67, P =.0102). Multivariate analyses supported this OS benefit (HR: 0.66). In the remaining patients (Group 2; n = 696), a 5.2-month PFS extension was observed in bevacizumab-treated patients (HR: 0.61, P<.0001); OS was comparable between the treatment arms (HR: 0.88, P =.1502). No significant differences in safety were observed between the 2 groups. Conclusion: This exploratory analysis suggests that the addition of bevacizumab to standard glioblastoma treatment prolongs PFS and OS for patients with PD who receive only one line of therapy.

  • 249. Chinot, Olivier L.
    et al.
    Taphoorn, Martin J. B.
    Bais, Carlos
    Bourgon, Richard
    Phillips, Heidi S.
    Abrey, Lauren E.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regional Cancer Center Stockholm, Stockholm.
    Saran, Frank
    Nishikawa, Ryo
    Cloughesy, Timothy
    Identification of Patients Who Benefit From Bevacizumab in High-Grade Glioma-An Easy Question Turned Difficult: Treat the Scan or the Patient? Reply2016In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 11, p. 1282-1283Article in journal (Other academic)
  • 250. Chinot, Olivier L.
    et al.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Reg Canc Ctr Stockholm,.
    Saran, Frank
    Nishikawa, Ryo
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana
    Brandes, Alba A.
    Hilton, Magalie
    Kerloeguen, Yannick
    Guijarro, Abajo
    Cloughsey, Timothy
    FINAL EFFICACY AND SAFETY RESULTS FROM AVAglio, A PHASE III TRIAL OF BEVACIZUMAB (BEV) PLUS TEMOZOLOMIDE (TMZ) ANDRADIOTHERAPY (RT) IN NEWLY DIAGNOSED GLIOBLASTOMA2013In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, no Supplement: 3, p. 105-106Article in journal (Other academic)
2345678 201 - 250 of 1692
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