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  • 51. Honda, Kazufumi
    et al.
    Katzke, Verena A.
    Hüsing, Anika
    Okaya, Shinobu
    Shoji, Hirokazu
    Onidani, Kaoru
    Olsen, Anja
    Tjønneland, Anne
    Overvad, Kim
    Weiderpass, Elisabete
    Vineis, Paolo
    Muller, David
    Tsilidis, Kostas
    Palli, Domenico
    Pala, Valeria
    Tumino, Rosario
    Naccarati, Alessio
    Panico, Salvatore
    Aleksandrova, Krasimira
    Boeing, Heiner
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H.
    Trichopoulou, Antonia
    Lagiou, Pagona
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C.
    Merino, Susana
    Duell, Eric J.
    Rodríguez-Barranco, Miguel
    Chirlaque, María Dolores
    Barricarte, Aurelio
    Rebours, Vinciane
    Boutron-Ruault, Marie-Chiristine
    Romana Mancini, Francesca
    Brennan, Paul
    Scelo, Ghislaine
    Manjer, Jonas
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Öhlund, Daniel
    Canzian, Federico
    Kaaks, Rudolf
    CA19-9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer: a prospective evaluation2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 8, p. 1877-1887Article in journal (Refereed)
    Abstract [en]

    Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. Our study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤ 18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤ 18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.

  • 52. Jacobs, Eric J
    et al.
    Chanock, Stephen J
    Fuchs, Charles S
    Lacroix, Andrea
    McWilliams, Robert R
    Steplowski, Emily
    Stolzenberg-Solomon, Rachael Z
    Arslan, Alan A
    Bueno-de-Mesquita, H Bas
    Gross, Myron
    Helzlsouer, Kathy
    Petersen, Gloria
    Zheng, Wei
    Agalliu, Ilir
    Allen, Naomi E
    Amundadottir, Laufey
    Boutron-Ruault, Marie-Christine
    Buring, Julie E
    Canzian, Federico
    Clipp, Sandra
    Dorronsoro, Miren
    Gaziano, J Michael
    Giovannucci, Edward L
    Hankinson, Susan E
    Hartge, Patricia
    Hoover, Robert N
    Hunter, David J
    Jacobs, Kevin B
    Jenab, Mazda
    Kraft, Peter
    Kooperberg, Charles
    Lynch, Shannon M
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Mendelsohn, Julie B
    Mouw, Tracy
    Newton, Christina C
    Overvad, Kim
    Palli, Domenico
    Peeters, Petra H M
    Rajkovic, Aleksandar
    Shu, Xiao-Ou
    Thomas, Gilles
    Tobias, Geoffrey S
    Trichopoulos, Dimitrios
    Virtamo, Jarmo
    Wactawski-Wende, Jean
    Wolpin, Brian M
    Yu, Kai
    Zeleniuch-Jacquotte, Anne
    Family history of cancer and risk of pancreatic cancer: A pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan).2010In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed)
    Abstract [en]

    A family history of pancreatic cancer has consistently been associated with increased risk of pancreatic cancer. However, uncertainty remains about the strength of this association. Results from previous studies suggest a family history of select cancers (i.e., ovarian, breast and colorectal) could also be associated, although not as strongly, with increased risk of pancreatic cancer. We examined the association between a family history of 5 types of cancer (pancreas, prostate, ovarian, breast and colorectal) and risk of pancreatic cancer using data from a collaborative nested case-control study conducted by the Pancreatic Cancer Cohort Consortium. Cases and controls were from cohort studies from the United States, Europe and China, and a case-control study from the Mayo Clinic. Analyses of family history of pancreatic cancer included 1,183 cases and 1,205 controls. A family history of pancreatic cancer in a parent, sibling or child was associated with increased risk of pancreatic cancer [multivariate-adjusted odds ratios (ORs) = 1.76, 95% confidence interval (CI) = 1.19-2.61]. A family history of prostate cancer was also associated with increased risk (OR = 1.45, 95% CI = 1.12-1.89). There were no statistically significant associations with a family history of ovarian cancer (OR = 0.82, 95% CI = 0.52-1.31), breast cancer (OR = 1.21, 95% CI = 0.97-1.51) or colorectal cancer (OR = 1.17, 95% CI = 0.93-1.47). Our results confirm a moderate sized association between a family history of pancreatic cancer and risk of pancreatic cancer and also provide evidence for an association with a family history of prostate cancer worth further study.

  • 53. Javed, Muhammad Ahsan
    et al.
    Beyer, Georg
    Le, Nha
    Vinci, Alessio
    Wong, Helen
    Palmer, Daniel
    Morgan, Robert D
    Lamarca, Angela
    Hubner, Richard A
    Valle, Juan W
    Alam, Salma
    Chowdhury, Sumsur
    Ma, Yuk Ting
    Archibugi, Livia
    Capurso, Gabriele
    Maisonneuve, Patrick
    Neesse, Albrecht
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Schober, Marvin
    Krug, Sebastian
    Impact of intensified chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical routine in Europe2019In: Pancreatology (Print), ISSN 1424-3903, E-ISSN 1424-3911, Vol. 19, no 1, p. 97-104Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma (MPA). Randomized clinical trials evaluating intensified chemotherapies including FOLFIRINOX and nab-paclitaxel plus gemcitabine (NAB+GEM) have shown improvement in survival. Here, we have evaluated the efficacy of intensified chemotherapy versus gemcitabine monotherapy in real-life settings across Europe.

    METHODS: A retrospective multi-center study including 1056 MPA patients, between 2012 and 2015, from nine centers in UK, Germany, Italy, Hungary and the Swedish registry was performed. Follow-up was at least 12 months. Cox proportional Harzards regression was used for uni- and multivariable evaluation of prognostic factors.

    RESULTS: Of 1056 MPA patients, 1030 (98.7%) were assessable for survival analysis. Gemcitabine monotherapy was the most commonly used regimen (41.3%), compared to FOLFIRINOX (n = 204, 19.3%), NAB+GEM (n = 81, 7.7%) and other gemcitabine- or 5-FU-based regimens (n = 335, 31.7%). The median overall survival (OS) was: FOLFIRINOX 9.9 months (95%CI 8.4-12.6), NAB+GEM 7.9 months (95%CI 6.2-10.0), other combinations 8.5 months (95%CI 7.7-9.3) and gemcitabine monotherapy 4.9 months (95%CI 4.4-5.6). Compared to gemcitabine monotherapy, any combination of chemotherapeutics improved the survival with no significant difference between the intensified regimens. Multivariable analysis showed an association between treatment center, male gender, inoperability at diagnosis and performance status (ECOG 1-3) with poor prognosis.

    CONCLUSION: Gemcitabine monotherapy was predominantly used in 2012-2015. Intensified chemotherapy improved OS in comparison to gemcitabine monotherapy. In real-life settings, the OS rates of different treatment approaches are lower than shown in randomized phase III trials.

  • 54. Jeurnink, Suzanne M.
    et al.
    Ros, Martine M.
    Leenders, Max
    van Duijnhoven, Franzel J. B.
    Siersema, Peter D.
    Jansen, Eugene H. J. M.
    van Gils, Carla H.
    Bakker, Marije F.
    Overvad, Kim
    Roswall, Nina
    Tjonneland, Anne
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Cadeau, Claire
    Grote, Verena
    Kaaks, Rudolf
    Aleksandrova, Krasimira
    Boeing, Heiner
    Trichopoulou, Antonia
    Benetou, Vasiliki
    Valanou, Elisavet
    Palli, Domenico
    Krogh, Vittorio
    Vineis, Paolo
    Tumino, Rosario
    Mattiello, Amalia
    Weiderpass, Elisabete
    Skeie, Guri
    Huerta Castano, Jose Maria
    Duell, Eric J.
    Barricarte, Aurelio
    Molina-Montes, Esther
    Argueelles, Marcial
    Dorronsoro, Mire
    Johansen, Dorthe
    Lindkvist, Bjorn
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Crowe, Francesca L.
    Khaw, Kay-Tee
    Jenab, Mazda
    Fedirko, Veronika
    Riboli, E.
    Bueno-de-Mesquita, H. B(as)
    Plasma carotenoids, vitamin C, retinol and tocopherols levels and pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition: A nested case-control study Plasma micronutrients and pancreatic cancer risk2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 6, p. E665-E676Article in journal (Refereed)
    Abstract [en]

    Evidence of a protective effect of several antioxidants and other nutrients on pancreatic cancer risk is inconsistent. The aim of this study was to investigate the association for prediagnostic plasma levels of carotenoids, vitamin C, retinol and tocopherols with risk of pancreatic cancer in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). 446 incident exocrine pancreatic cancer cases were matched to 446 controls by age at blood collection, study center, sex, date and time of blood collection, fasting status and hormone use. Plasma carotenoids (- and -carotene, lycopene, -cryptoxanthin, canthaxanthin, zeaxanthin and lutein), - and -tocopherol and retinol were measured by reverse phase high-performance liquid chromatography and plasma vitamin C by a colorimetric assay. Incidence rate ratios (IRRs) with 95% confidence intervals (95%CIs) for pancreatic cancer risk were estimated using a conditional logistic regression analysis, adjusted for smoking status, smoking duration and intensity, waist circumference, cotinine levels and diabetes status. Inverse associations with pancreatic cancer risk were found for plasma -carotene (IRR highest vs. lowest quartile 0.52, 95%CI 0.31-0.88, p for trend=0.02), zeaxanthin (IRR highest vs. lowest quartile 0.53, 95%CI 0.30-0.94, p for trend=0.06) and -tocopherol (IRR highest vs. lowest quartile 0.62, 95%CI 0.39-0.99, p for trend=0.08. For - and -carotene, lutein, sum of carotenoids and -tocopherol, heterogeneity between geographical regions was observed. In conclusion, our results show that higher plasma concentrations of -carotene, zeaxanthin and -tocopherol may be inversely associated with risk of pancreatic cancer, but further studies are warranted. What's new? Fruits and vegetables may play a role in the prevention of pancreatic cancer, but associations between the antioxidants those foods contain and disease risk remain unclear. In this study, pancreatic cancer risk was inversely associated with increased prediagnostic plasma concentrations of the antioxidants -carotene, zeaxanthin, and -tocopherol. Geographic variations were also detected. In Northern European countries, inverse associations with risk were found for blood levels of several carotenoids, whereas the association was strongest for -tocopherol in Southern European countries. The role of carotenoids and vitamins should be considered in subsequent investigations of the etiology of pancreatic cancer.

  • 55. Johansson, J.
    et al.
    Berg, T.
    Kurzejamska, E.
    Pang, M-F
    Tabor, V.
    Jansson, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Roswall, P.
    Pietras, K.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Religa, P.
    Fuxe, J.
    MiR-155-mediated loss of C/EBP beta shifts the TGF-beta response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer2013In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 50, p. 5614-5624Article in journal (Refereed)
    Abstract [en]

    During breast cancer progression, transforming growth factor-beta (TGF-beta) switches from acting as a growth inhibitor to become a major promoter of epithelial-mesenchymal transition (EMT), invasion and metastasis. However, the mechanisms involved in this switch are not clear. We found that loss of CCAAT-enhancer binding protein beta (C/EBP beta), a differentiation factor for the mammary epithelium, was associated with signs of EMT in triple-negative human breast cancer, and in invasive areas of mammary tumors in MMTV-PyMT mice. Using an established model of TGF-beta-induced EMT in mouse mammary gland epithelial cells, we discovered that C/EBP beta was repressed during EMT by miR-155, an oncomiR in breast cancer. Depletion of C/EBP beta potentiated the TGF-beta response towards EMT, and contributed to evasion of the growth inhibitory response to TGF-beta. Furthermore, loss of C/EBP beta enhanced invasion and metastatic dissemination of the mouse mammary tumor cells to the lungs after subcutaneous injection into mice. The mechanism by which loss of C/EBP beta promoted the TGF-beta response towards EMT, invasion and metastasis, was traced to a previously uncharacterized role of C/EBP beta as a transcriptional activator of genes encoding the epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor. The results identify miR-155-mediated loss of C/EBP beta as a mechanism, which promotes breast cancer progression by shifting the TGF-beta response from growth inhibition to EMT, invasion and metastasis.

  • 56. Joshi, Amit D.
    et al.
    Lindström, Sara
    Hüsing, Anika
    Barrdahl, Myrto
    VanderWeele, Tyler J.
    Campa, Daniele
    Canzian, Federico
    Gaudet, Mia M.
    Figueroa, Jonine D.
    Baglietto, Laura
    Berg, Christine D.
    Buring, Julie E.
    Chanock, Stephen J.
    Chirlaque, María-Dolores
    Diver, W. Ryan
    Dossus, Laure
    Giles, Graham G.
    Haiman, Christopher A.
    Hankinson, Susan E.
    Henderson, Brian E.
    Hoover, Robert N.
    Hunter, David J.
    Isaacs, Claudine
    Kaaks, Rudolf
    Kolonel, Laurence N.
    Krogh, Vittorio
    Le Marchand, Loic
    Lee, I-Min
    Lund, Eiliv
    McCarty, Catherine A.
    Overvad, Kim
    Peeters, Petra H.
    Riboli, Elio
    Schumacher, Fredrick
    Severi, Gianluca
    Stram, Daniel O.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Thun, Michael J.
    Travis, Ruth C.
    Trichopoulos, Dimitrios
    Willett, Walter C.
    Zhang, Shumin
    Ziegler, Regina G.
    Kraft, Peter
    Additive interactions between susceptibility single-nucleotide polymorphisms identified in genome-wide association studies and breast cancer risk factors in the Breast and Prostate Cancer Cohort Consortium2014In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 180, no 10, p. 1018-1027Article in journal (Refereed)
    Abstract [en]

    Additive interactions can have public health and etiological implications but are infrequently reported. We assessed departures from additivity on the absolute risk scale between 9 established breast cancer risk factors and 23 susceptibility single-nucleotide polymorphisms (SNPs) identified from genome-wide association studies among 10,146 non-Hispanic white breast cancer cases and 12,760 controls within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. We estimated the relative excess risk due to interaction and its 95% confidence interval for each pairwise combination of SNPs and nongenetic risk factors using age- and cohort-adjusted logistic regression models. After correction for multiple comparisons, we identified a statistically significant relative excess risk due to interaction (uncorrected P = 4.51 x 10(-5)) between a SNP in the DNA repair protein RAD51 homolog 2 gene (RAD51L1; rs10483813) and body mass index (weight (kg)/height (m)(2)). We also compared additive and multiplicative polygenic risk prediction models using per-allele odds ratio estimates from previous studies for breast-cancer susceptibility SNPs and observed that the multiplicative model had a substantially better goodness of fit than the additive model.

  • 57. Kaaks, Rudolf
    et al.
    Johnson, Theron
    Tikk, Kaja
    Sookthai, Disorn
    Tjønneland, Anne
    Roswall, Nina
    Overvad, Kim
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Rinaldi, Sabina
    Romieu, Isabelle
    Boeing, Heiner
    Schütze, Madlen
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Grioni, Sara
    Tumino, Rosario
    Sacerdote, Carlotta
    Panico, Salvatore
    Buckland, Genevieve
    Argüelles, Marcial
    Sánchez, María-José
    Amiano, Pilar
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Bueno-de-Mesquita, H Bas
    van Gils, Carla H
    Peeters, Petra H
    Andersson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Weiderpass, Elisabete
    Gram, Inger Torhild
    Lund, Eiliv
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J
    Travis, Ruth C
    Merritt, Melissa A
    Gunter, Marc J
    Riboli, Elio
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Insulin-like growth factor I and risk of breast cancer by age and hormone receptor status: A prospective study within the EPIC cohort2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 11, p. 2683-2690Article in journal (Refereed)
    Abstract [en]

    Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case–control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR)Q4-Q1 = 1.41 [95% confidence interval (CI) 1.01–1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04–1.33] per 1-standard deviation (SD) increase in IGF-I, ptrend = 0.01) and among women who were diagnosed with breast cancer at 50 years or older (ORQ3-Q1 = 1.38 [95% CI 1.01–1.89]; OR = 1.19 [95% CI 1.04–1.36] per 1-SD increase in IGF-I, ptrend = 0.01) but not with receptor-positive disease diagnosed at an earlier age. No statistically significant associations were observed for ER− breast tumors overall and by age at diagnosis. Tests for heterogeneity by receptor status of the tumor were not statistically significant, except for women diagnosed with breast cancer at 50 years or older (phet = 0.03 for ER+/PR+ vs. ER−/PR− disease). Our data add to a global body of evidence indicating that higher circulating IGF-I levels may increase risk specifically of receptor-positive, but not receptor-negative, breast cancer diagnosed at 50 years or older.

  • 58. Kaaks, Rudolf
    et al.
    Tikk, Kaja
    Sookthai, Disorn
    Schock, Helena
    Johnson, Theron
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Clavel-Chapelon, Francoise
    Dossus, Laure
    Baglietto, Laura
    Rinaldi, Sabina
    Chajes, Veronique
    Romieu, Isabelle
    Boeing, Heiner
    Schuetze, Madlen
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Ricceri, Fulvio
    Mattiello, Amalia
    Buckland, Genevieve
    Ramon Quiros, Jose
    Sanchez, Maria-Jose
    Amiano, Pilar
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Bas Bueno-de-Mesquita, H.
    van Gils, Carla H.
    Peeters, Petra H.
    Andersson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Weiderpass, Elisabete
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Travis, Ruth C.
    Merritt, Melissa A.
    Gunter, Marc J.
    Riboli, Elio
    Lukanova-McGregor, Annekatrin
    Premenopausal serum sex hormone levels in relation to breast cancer risk, overall and by hormone receptor status-Results from the EPIC cohort2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 8, p. 1947-1957Article in journal (Refereed)
    Abstract [en]

    Results from prospective studies on premenopausal serum hormone levels in relation to breast cancer risk have been inconclusive, especially with regard to tumor subtypes. Using a case-control study nested within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (801 breast cancer cases and 1,132 matched control subjects), we analyzed the relationships of prediagnostic serum estradiol, free estradiol, progesterone, testosterone, free testosterone and sex hormone-binding globulin (SHBG) levels with the risk of breast cancer by estrogen and progesterone receptor-positive and -negative breast tumors and by age at diagnoses. Higher prediagnostic serum levels of testosterone and free testosterone were associated with an increased overall risk of breast cancer [ORQ4-Q1=1.56 (95% CI 1.15-2.13), p(trend)=0.02 for testosterone and ORQ4-Q1=1.33 (95% CI 0.99-1.79), p(trend)=0.04 for free testosterone], but no significant risk association was observed for estradiol, free estradiol, progesterone and SHBG. Tests for heterogeneity between receptor-positive and -negative tumors were not significant. When analysis were stratified by age at tumor diagnosis, the odds ratios observed for estradiol were stronger and borderline significant for breast cancer diagnosed at age less than 50 [ORQ4-Q1=1.32 (95% CI 0.87-2.01), p(trend)=0.05] compared to breast cancer diagnosed at age 50 or above [ORQ4-Q1=0.94 (95% CI 0.60-1.47), p(trend)=0.34, p(het)=0.04]. In conclusion, our data indicate that higher premenopausal circulating testosterone levels are associated with an increased risk of developing breast cancer, but do not show a significant association of estradiol or progesterone with breast cancer risk, overall, by menstrual cycle phase or by tumor receptor status, although a possible risk increase with higher estradiol levels for tumors diagnosed before age 50 was seen.

  • 59. Karakatsanis, A.
    et al.
    Oloffson, H.
    Bergkvist, L. A.
    Abdsaleh, S.
    Sund, Malin
    Warnberg, F.
    How to avoid unnecessary sentinel node biopsy in patients with ductal cancer in situ2015In: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 24 1, p. S133-S134Article in journal (Other academic)
  • 60. Klein, Alison P.
    et al.
    Wolpin, Brian M.
    Risch, Harvey A.
    Stolzenberg-Solomon, Rachael Z.
    Mocci, Evelina
    Zhang, Mingfeng
    Canzian, Federico
    Childs, Erica J.
    Hoskins, Jason W.
    Jermusyk, Ashley
    Zhong, Jun
    Chen, Fei
    Albanes, Demetrius
    Andreotti, Gabriella
    Arslan, Alan A.
    Babic, Ana
    Bamlet, William R.
    Beane-Freeman, Laura
    Berndt, Sonja I.
    Blackford, Amanda
    Borges, Michael
    Borgida, Ayelet
    Bracci, Paige M.
    Brais, Lauren
    Brennan, Paul
    Brenner, Hermann
    Bueno-de-Mesquita, Bas
    Buring, Julie
    Campa, Daniele
    Capurso, Gabriele
    Cavestro, Giulia Martina
    Chaffee, Kari G.
    Chung, Charles C.
    Cleary, Sean
    Cotterchio, Michelle
    Dijk, Frederike
    Duell, Eric J.
    Foretova, Lenka
    Fuchs, Charles
    Funel, Niccola
    Gallinger, Steven
    Gaziano, J. Michael M.
    Gazouli, Maria
    Giles, Graham G.
    Giovannucci, Edward
    Goggins, Michael
    Goodman, Gary E.
    Goodman, Phyllis J.
    Hackert, Thilo
    Haiman, Christopher
    Hartge, Patricia
    Hasan, Manal
    Hegyi, Peter
    Helzlsouer, Kathy J.
    Herman, Joseph
    Holcatova, Ivana
    Holly, Elizabeth A.
    Hoover, Robert
    Hung, Rayjean J.
    Jacobs, Eric J.
    Jamroziak, Krzysztof
    Janout, Vladimir
    Kaaks, Rudolf
    Khaw, Kay-Tee
    Klein, Eric A.
    Kogevinas, Manolis
    Kooperberg, Charles
    Kulke, Matthew H.
    Kupcinskas, Juozas
    Kurtz, Robert J.
    Laheru, Daniel
    Landi, Stefano
    Lawlor, Rita T.
    Lee, I. -Min
    LeMarchand, Loic
    Lu, Lingeng
    Malats, Nuria
    Mambrini, Andrea
    Mannisto, Satu
    Milne, Roger L.
    Mohelnikova-Duchonova, Beatrice
    Neale, Rachel E.
    Neoptolemos, John P.
    Oberg, Ann L.
    Olson, Sara H.
    Orlow, Irene
    Pasquali, Claudio
    Patel, Alpa V.
    Peters, Ulrike
    Pezzilli, Raffaele
    Porta, Miquel
    Real, Francisco X.
    Rothman, Nathaniel
    Scelo, Ghislaine
    Sesso, Howard D.
    Severi, Gianluca
    Shu, Xiao-Ou
    Silverman, Debra
    Smith, Jill P.
    Soucek, Pavel
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Talar-Wojnarowska, Renata
    Tavano, Francesca
    Thornquist, Mark D.
    Tobias, Geoffrey S.
    Van Den Eeden, Stephen K.
    Vashist, Yogesh
    Visvanathan, Kala
    Vodicka, Pavel
    Wactawski-Wende, Jean
    Wang, Zhaoming
    Wentzensen, Nicolas
    White, Emily
    Yu, Herbert
    Yu, Kai
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Kraft, Peter
    Li, Donghui
    Chanock, Stephen
    Obazee, Ofure
    Petersen, Gloria M.
    Amundadottir, Laufey T.
    Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 556Article in journal (Refereed)
    Abstract [en]

    In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 x 10(-8)). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PAN-DoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 x 10(-14)), rs2941471 at 8q21.11 (HNF4G, P = 6.60 x 10(-10)), rs4795218 at 17q12 (HNF1B, P = 1.32 x 10(-8)), and rs1517037 at 18q21.32 (GRP, P = 3.28 x 10(-8)). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

  • 61. Krug, S.
    et al.
    Beyer, G.
    Javed, M. A.
    Le, N.
    Vinci, A.
    Morgan, R. D.
    Hubner, R.
    Valle, J. W.
    Wong, H.
    Chowdhury, S.
    Ma, Y. Ting
    Palmer, D.
    Maisonneuve, P.
    Neesse, A.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Schober, M.
    Intensified chemotherapy for metastatic pancreatic cancer: interim analysis of a large retrospective pan-European database and real life evaluation2016In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 27Article in journal (Refereed)
  • 62. Kyrø, Cecilie
    et al.
    Zamora-Ros, Raul
    Scalbert, Augustin
    Tjønneland, Anne
    Dossus, Laure
    Johansen, Christoffer
    Bidstrup, Pernille Envold
    Weiderpass, Elisabete
    Christensen, Jane
    Ward, Heather
    Aune, Dagfinn
    Riboli, Elio
    His, Mathilde
    Clavel-Chapelon, Françoise
    Baglietto, Laura
    Katzke, Verena
    Kühn, Tilman
    Boeing, Heiner
    Floegel, Anna
    Overvad, Kim
    Lasheras, Cristina
    Travier, Noémie
    Sánchez, Maria-José
    Amiano, Pilar
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nick
    Perez-Cornago, Aurora
    Trichopoulou, Antonia
    Lagiou, Pagona
    Vasilopoulou, Effie
    Masala, Giovanna
    Grioni, Sara
    Berrino, Franco
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Bueno-de-Mesquita, H B(as)
    Peeters, Petra H
    van Gils, Carla
    Borgquist, Signe
    Butt, Salma
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hjartåker, Anette
    Skeie, Guri
    Olsen, Anja
    Romieu, Isabelle
    Pre-diagnostic polyphenol intake and breast cancer survival: the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2015In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 154, no 2, p. 389-401Article in journal (Refereed)
    Abstract [en]

    The aim was to investigate the association between pre-diagnostic intakes of polyphenol classes (flavonoids, lignans, phenolic acids, stilbenes, and other polyphenols) in relation to breast cancer survival (all-cause and breast cancer-specific mortality). We used data from the European Prospective Investigation into Cancer and Nutrition cohort. Pre-diagnostic usual diet was assessed using dietary questionnaires, and polyphenol intakes were estimated using the Phenol-Explorer database. We followed 11,782 breast cancer cases from time of diagnosis until death, end of follow-up or last day of contact. During a median of 6 years, 1482 women died (753 of breast cancer). We related polyphenol intake to all-cause and breast cancer-specific mortality using Cox proportional hazard models with time since diagnosis as underlying time and strata for age and country. Among postmenopausal women, an intake of lignans in the highest versus lowest quartile was related to a 28 % lower risk of dying from breast (adjusted model: HR, quartile 4 vs. quartile 1, 0.72, 95 % CI 0.53; 0.98). In contrast, in premenopausal women, a positive association between lignan intake and all-cause mortality was found (adjusted model: HR, quartile 4 vs. quartile 1, 1.63, 95 % CI 1.03; 2.57). We found no association for other polyphenol classes. Intake of lignans before breast cancer diagnosis may be related to improved survival among postmenopausal women, but may on the contrary worsen the survival for premenopausal women. This suggests that the role of phytoestrogens in breast cancer survival is complex and may be dependent of menopausal status.

  • 63. Kühn, Tilman
    et al.
    Kaaks, Rudolf
    Becker, Susen
    Eomois, Piia-Piret
    Clavel-Chapelon, Françoise
    Kvaskoff, Marina
    Dossus, Laure
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Chang-Claude, Jenny
    Lukanova, Annekatrin
    Buijsse, Brian
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Bamia, Christina
    Masala, Giovanna
    Krogh, Vittorio
    Sacerdote, Carlotta
    Tumino, Rosario
    Mattiello, Amalia
    Buckland, Genevieve
    Sánchez, María-José
    Menéndez, Virginia
    Chirlaque, María-Dolores
    Barricarte, Aurelio
    Bueno-de-Mesquita, H Bas
    van Duijnhoven, Fränzel J B
    van Gils, Carla H
    Bakker, Marije F
    Weiderpass, Elisabete
    Skeie, Guri
    Brustad, Magritt
    Andersson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Wareham, Nick
    Khaw, Kay Tee
    Travis, Ruth C
    Schmidt, Julie A
    Rinaldi, Sabina
    Romieu, Isabelle
    Gallo, Valentina
    Murphy, Neil
    Riboli, Elio
    Linseisen, Jakob
    Plasma 25-hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: A nested case-control study2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 7, p. 1689-1700Article in journal (Refereed)
    Abstract [en]

    Experimental evidence suggests that vitamin D might play a role in the development of breast cancer. Although the results of case-control studies indicate that circulating 25-hydroxyvitamin D [25(OH)D] is inversely associated with the risk of breast cancer, the results of prospective studies are inconsistent. A case-control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) was carried out comprising 1,391 incident breast cancer cases and 1,391 controls. Multivariable conditional logistic regression models did not reveal a significant overall association between season-standardized 25(OH)D levels and the risk of breast cancer (ORQ4-Q1 [95% CI]: 1.07 [0.85-1.36], ptrend = 0.67). Moreover, 25(OH)D levels were not related to the risks of estrogen receptor positive tumors (ORQ4-Q1 [95% CI]: 0.97 [0.67-1.38], ptrend = 0.90) and estrogen receptor negative tumors (ORQ4-Q1 [95% CI]: 0.97 [0.66-1.42], ptrend = 0.98). In hormone replacement therapy (HRT) users, 25(OH)D was significantly inversely associated with incident breast cancer (ORlog2 [95% CI]: 0.62 [0.42-0.90], p = 0.01), whereas no significant association was found in HRT nonusers (ORlog2 [95% CI]: 1.14 [0.80-1.62], p = 0.48). Further, a nonsignificant inverse association was found in women with body mass indices (BMI) < 25 kg/m(2) (ORlog2 [95% CI]: 0.83 [0.67-1.03], p = 0.09), as opposed to a borderline significant positive association in women with BMI ≥ 25 kg/m(2) (ORlog2 [95% CI]: 1.30 [1.0-1.69], p = 0.05). Overall, prediagnostic levels of circulating 25(OH)D were not related to the risk of breast cancer in the EPIC study. This result is in line with findings in the majority of prospective studies and does not support a role of vitamin D in the development of breast cancer.

  • 64. Le, Nha
    et al.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Vinci, Alessio
    Prognostic and predictive markers in pancreatic adenocarcinoma2016In: Digestive and Liver Disease, ISSN 1590-8658, E-ISSN 1878-3562, Vol. 48, no 3, p. 223-230Article, review/survey (Refereed)
    Abstract [en]

    Pancreatic ductal adenocarcinoma is characterized by a poor prognosis and a low median survival, despite improvements observed for many other solid tumours. Intensive research efforts have been undertaken during the last decades to discover new prognostic and treatment predictive biomarkers for pancreatic ductal adenocarcinoma. The mainstay of medical treatment for the disease has been the well-tolerated nucleoside analogue, gemcitabine. The only targeted agent currently used in pancreatic ductal adenocarcinoma patients is the epithelial growth factor receptor inhibitor erlotinib in combination with gemcitabine. Recently, treatment regimens such as a combination of fluorouracilleucovorin-irinotecan-oxaliplatin (FOLFIRINOX) and the combination of nab-paclitaxel with gemcitabine have been introduced for metastatic pancreatic ductal adenocarcinoma. Although these treatment regimens significantly improve survival of patients, there are no good predictive biomarkers available that can be used to identify who would benefit most from them. Therefore, the search for predictive biomarkers that would facilitate personalization of chemotherapy is highly relevant.

  • 65. Le, Nha
    et al.
    Vinci, Alessio
    Schober, Marvin
    Krug, Sebastian
    Javed, Muhammad A.
    Kohlmann, Thomas
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Neesse, Albrecht
    Beyer, Georg
    Real-world clinical practice of intensified chemotherapies for metastatic pancreatic cancer: results from a Pan-European questionnaire study2016In: Digestion, ISSN 0012-2823, E-ISSN 1421-9867, Vol. 94, no 4, p. 222-229Article in journal (Refereed)
    Abstract [en]

    Introduction: Recently, FOLFIRINOX and gemcitabine + nab-paclitaxel have been introduced as a novel intensified chemotherapy regimen for patients with metastasized pancreatic cancer. This study aims to analyze the real-world clinical practice with FOLFIRINOX and gemcitabine + nab-paclitaxel across Europe.

    Methods: Invitations to participate in an anonymous web-based questionnaire were sent via e-mail to 5,420 doctors in 19 European countries through the network of national gastroenterological, oncological, surgical and pancreatic societies as well as the European Pancreatic Club. The questionnaire consisted of 20 questions, 14 regarding the use of intensified chemotherapy, 4 regarding demographics of the participants, and 1 to verify the active involvement in the management of metastatic pancreatic cancer.

    Results: Two hundred and thirteen responses were received and 153 entries were valid for analysis. Of those, 63.4% came from an academic institution, 51% were oncologists, and 52% treated more than 25 cases per year. A majority of responses (71%) were from Italy (40%), Germany (23%), and Spain (8%). As first-line therapy, 11% used gemcitabine +/- erlotinib, 42% used FOLFIRINOX, and 47% used gemcitabine + nab-paclitaxel. Of the intensified regimens, both were applied to equal parts, but the likelihood of protocol deviation was higher when using FOLFIRINOX (p < 0.01). FOLFIRINOX was considered more toxic than gemcitabine + nab-paclitaxel (neutropenia 88 vs. 68%; polyneuropathy 42 vs. 41%; rapid deterioration 42 vs. 31%). FOLFIRINOX was rated to achieve longer survival with an acceptable quality of life (52 vs. 44%). Moreover, 57% of participants thought that gemcitabine + nab-paclitaxel should be the backbone for further clinical trials in pancreatic cancer.

    Conclusion: Intensified chemotherapy is widely used in pancreatic cancer patients in Europe following its recent clinical approval. Interestingly, nab-paclitaxel and FOLFIRINOX were used at comparable frequency although the latter had to be de-escalated more often.

  • 66. LeBleu, Valerie
    et al.
    Sund, Malin
    Sugimoto, Hikaru
    Birrane, Gabriel
    Kanasaki, Keizo
    Finan, Elizabeth
    Miller, Caroline A
    Gattone, Vincent H
    McLaughlin, Heather
    Shield, Charles F
    Kalluri, Raghu
    Identification of the NC1 domain of α3 chain as critical for α3α4α5 type IV collagen network assembly2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 53, p. 41874-41885Article in journal (Refereed)
    Abstract [en]

    The network organization of type IV collagen consisting of α3, α4, and α5 chains in the glomerular basement membrane (GBM) is speculated to involve interactions of the triple helical and NC1 domain of individual α-chains, but in vivo evidence is lacking. To specifically address the contribution of the NC1 domain in the GBM collagen network organization, we generated a mouse with specific loss of α3NC1 domain while keeping the triple helical α3 chain intact by connecting it to the human α5NC1 domain. The absence of α3NC1 domain leads to the complete loss of the α4 chain. The α3 collagenous domain is incapable of incorporating the α5 chain, resulting in the impaired organization of the α3α4α5 chain-containing network. Although the α5 chain can assemble with the α1, α2, and α6 chains, such assembly is incapable of functionally replacing the α3α4α5 protomer. This novel approach to explore the assembly type IV collagen in vivo offers novel insights in the specific role of the NC1 domain in the assembly and function of GBM during health and disease.

  • 67. Leenders, Max
    et al.
    Chuang, Shu-Chun
    Dahm, Christina C
    Overvad, Kim
    Ueland, Per Magne
    Midttun, Oivind
    Vollset, Stein Emil
    Tjønneland, Anne
    Halkjaer, Jytte
    Jenab, Mazda
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Kaaks, Rudolf
    Canzian, Federico
    Boeing, Heiner
    Weikert, Cornelia
    Trichopoulou, Antonia
    Bamia, Christina
    Naska, Androniki
    Palli, Domenico
    Pala, Valeria
    Mattiello, Amalia
    Tumino, Rosario
    Sacerdote, Carlotta
    van Duijnhoven, Fränzel J B
    Peeters, Petra H M
    van Gils, Carla H
    Lund, Eiliv
    Rodriguez, Laudina
    Duell, Eric J
    Pérez, María-José Sánchez
    Molina-Montes, Esther
    Castaño, José María Huerta
    Barricarte, Aurelio
    Larrañaga, Nerea
    Johansen, Dorthe
    Lindkvist, Björn
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ye, Weimin
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Michaud, Dominique S
    Riboli, Elio
    Xun, Wei W
    Allen, Naomi E
    Crowe, Francesca L
    Bueno-de-Mesquita, H Bas
    Vineis, Paolo
    Plasma cotinine levels and pancreatic cancer in the EPIC cohort study.2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, no 4, p. 997-1002Article in journal (Refereed)
    Abstract [en]

    Smoking is an established risk factor for pancreatic cancer, previously investigated by the means of questionnaires. Using cotinine as a biomarker for tobacco exposure allows more accurate quantitative analyses to be performed. This study on pancreatic cancer, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC cohort), included 146 cases and 146 matched controls. Using liquid chromatography-mass spectrometry, plasma cotinine levels were analyzed on average 8.0 years before cancer onset (5-95% range: 2.8-12.0 years). The relation between plasma cotinine levels and pancreatic cancer was analyzed with conditional logistic regression for different levels of cotinine in a population of never and current smokers. This was also done for the self-reported number of smoked cigarettes per day at baseline. Every increase of 350 nmol/L of plasma cotinine was found to significantly elevate risk of pancreatic cancer [odds ratio (OR): 1.33, 95% confidence interval (CI): 1.11-1.60]. People with a cotinine level over 1187.8 nmol/L, a level comparable to smoking 17 cigarettes per day, have an elevated risk of pancreatic cancer, compared to people with cotinine levels below 55 nmol/L (OR: 3.66, 95% CI: 1.44-9.26). The results for self-reported smoking at baseline also show an increased risk of pancreatic cancer from cigarette smoking based on questionnaire information. People who smoke more than 30 cigarettes per day showed the highest risk compared to never smokers (OR: 4.15, 95% CI: 1.02-16.42). This study is the first to show that plasma cotinine levels are strongly related to pancreatic cancer.

  • 68. Li, Kuanrong
    et al.
    Anderson, Garnet
    Viallon, Vivian
    Arveux, Patrick
    Kvaskoff, Marina
    Fournier, Agnès
    Krogh, Vittorio
    Tumino, Rosario
    Sánchez, Maria-Jose
    Ardanaz, Eva
    Chirlaque, María-Dolores
    Agudo, Antonio
    Muller, David C
    Smith, Todd
    Tzoulaki, Ioanna
    Key, Timothy J
    Bueno-de-Mesquita, Bas
    Trichopoulou, Antonia
    Bamia, Christina
    Orfanos, Philippos
    Kaaks, Rudolf
    Hüsing, Anika
    Fortner, Renée T
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Population Health, New York University School of Medicine, New York, USA; Department of Environmental Medicine, New York University School of Medicine, New York, USA; Perlmutter Cancer Center, New York University School of Medicine, New York, USA.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Dahm, Christina C
    Overvad, Kim
    Aune, Dagfinn
    Weiderpass, Elisabete
    Romieu, Isabelle
    Riboli, Elio
    Gunter, Marc J
    Dossus, Laure
    Prentice, Ross
    Ferrari, Pietro
    Risk prediction for estrogen receptor-specific breast cancers in two large prospective cohorts2018In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 20, article id 147Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Few published breast cancer (BC) risk prediction models consider the heterogeneity of predictor variables between estrogen-receptor positive (ER+) and negative (ER-) tumors. Using data from two large cohorts, we examined whether modeling this heterogeneity could improve prediction.

    METHODS: We built two models, for ER+ (ModelER+) and ER- tumors (ModelER-), respectively, in 281,330 women (51% postmenopausal at recruitment) from the European Prospective Investigation into Cancer and Nutrition cohort. Discrimination (C-statistic) and calibration (the agreement between predicted and observed tumor risks) were assessed both internally and externally in 82,319 postmenopausal women from the Women's Health Initiative study. We performed decision curve analysis to compare ModelER+ and the Gail model (ModelGail) regarding their applicability in risk assessment for chemoprevention.

    RESULTS: Parity, number of full-term pregnancies, age at first full-term pregnancy and body height were only associated with ER+ tumors. Menopausal status, age at menarche and at menopause, hormone replacement therapy, postmenopausal body mass index, and alcohol intake were homogeneously associated with ER+ and ER- tumors. Internal validation yielded a C-statistic of 0.64 for ModelER+ and 0.59 for ModelER-. External validation reduced the C-statistic of ModelER+ (0.59) and ModelGail (0.57). In external evaluation of calibration, ModelER+ outperformed the ModelGail: the former led to a 9% overestimation of the risk of ER+ tumors, while the latter yielded a 22% underestimation of the overall BC risk. Compared with the treat-all strategy, ModelER+ produced equal or higher net benefits irrespective of the benefit-to-harm ratio of chemoprevention, while ModelGail did not produce higher net benefits unless the benefit-to-harm ratio was below 50. The clinical applicability, i.e. the area defined by the net benefit curve and the treat-all and treat-none strategies, was 12.7 × 10- 6 for ModelER+ and 3.0 × 10- 6 for ModelGail.

    CONCLUSIONS: Modeling heterogeneous epidemiological risk factors might yield little improvement in BC risk prediction. Nevertheless, a model specifically predictive of ER+ tumor risk could be more applicable than an omnibus model in risk assessment for chemoprevention.

  • 69.
    Lindahl, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Simonsson, Monika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Increased levels of macrophage-secreted Cathepsin S during Prostate Cancer progression in TRAMP mice and patients2009In: Cancer Genomics and Proteomics, ISSN ISSN 1109-6535, EISSN 1790-6245, Vol. 6, no 3, p. 149-159Article in journal (Refereed)
    Abstract [en]

    Background: Protein expression during prostate tumour progression in transgenic TRAMP mice was studied, with the aim of identifying proteins associated with tumour progression and castration resistant tumour growth. Materials and Methods: Protein expression was compared between normal mouse prostate, primary TRAMP tumours and peripheral metastases in long-term castrated TRAMP mice using 2-dimensional differential in-gel electrophoresis and MALDI TOF/TOF analysis. Results were verified with Western blot analysis and immunohisto-chemistry in the TRAMP model and samples from patients. Results: The active form of cathepsin S (Cat S) was identified as being significantly up-regulated in poorly differentiated TRAMP tumours and in castration-resistant metastases compared to normal mouse prostate and well-differentiated tumours. Increased Cat S levels were also found in high Gleason grade tumour areas in patients. Cat S was primarily expressed by tumour-infiltrating macrophages, as shown by double staining of Cat S and CD68 expressing cells. A significantly higher number of Cat S expressing macrophages was found in castration-resistant than in hormone naïve high grade tumours in patients. No relation was found between Cat S levels and suggested Cat S regulated, matrix-derived fragments of collagen IV or laminin 5 γ2. Conclusion: Macrophage-secreted Cat S levels increase during prostate cancer progression and could be an interesting target for therapy.

  • 70. Lujan-Barroso, Leila
    et al.
    González, Carlos Alberto
    Slimani, Nadia
    Obón-Santacana, Mireia
    Ferrari, Pietro
    Freisling, Heinz
    Overvad, Kim
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Katzke, Verena
    Kühn, Tilman
    Tjønneland, Anne
    Olsen, Anja
    Quirós, J Ramón
    Sánchez-Cantalejo, Emilio
    Amiano, Pilar
    Navarro, Carmen
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C
    Trichopoulou, Antonia
    Bamia, Christina
    Benetou, Vassiliki
    Saieva, Calogero
    Grioni, Sara
    Tumino, Rosario
    Vineis, Paolo
    Mattiello, Amalia
    Bueno-de-Mesquita, H Bas
    Siersema, Peter D
    Numans, Mattijs E
    Peeters, Petra H
    Ericson, Ulrika
    Wirfält, Elisabet
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Weiderpass, Elisabete
    Skeie, Guri
    Riboli, Elio
    Boeing, Heiner
    Duell, Eric J
    Dietary intake of acrylamide and esophageal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort2014In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 25, no 5, p. 639-646Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The relation between dietary acrylamide intake and esophageal cancer (EC) risk, including esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), has not been consistent. We evaluated the association between dietary acrylamide intake and EAC, ESCC, and overall EC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

    METHODS: Multivariate Cox proportional hazards models were used to estimate the HR and 95 % confidence interval (95 % CI). Since nonlinear relations were observed, HRs were displayed for quartiles of acrylamide intake in μg per day.

    RESULTS: After a mean follow-up of 11 years, 341 EC were identified, 142 of which were EAC, 176 ESCC, and 23 other histological types or not specified. An increase in EC risk was observed in the second and third quartiles (HRQ2vsQ1 1.75, 95 % CI 1.12-2.74; HRQ3vsQ1 1.66, 95 % CI 1.05-2.61), but not in the fourth quartile, and there was no evidence for a linear dose-response trend. HRs were similarly elevated but not statistically significant when ESCC and EAC were analyzed separately, due to the small number of cases observed. No associations were observed when quartiles were based on energy-adjusted acrylamide intake.

    CONCLUSIONS: In the EPIC cohort, an association between estimated dietary acrylamide intake and an increased risk of developing EC was observed in the middle quartiles but not in the highest quartile; however, results from other larger cohorts or consortia, and results from biomarker studies, might add to the evidence provided by this analysis, suggesting that acrylamide is not an important risk factor for EC.

  • 71.
    Lukanova, Annekatrin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
    Becker, Susen
    Hüsing, Anika
    Schock, Helena
    Fedirko, Veronika
    Trepo, Elisabeth
    Trichopoulou, Antonia
    Bamia, Christina
    Lagiou, Pagona
    Benetou, Vassiliki
    Trichopoulos, Dimitrios
    Nöthlings, Ute
    Tjønneland, Anne
    Overvad, Kim
    Dossus, Laure
    Teucher, Birgit
    Boeing, Heiner
    Aleksandrova, Krasimira
    Palli, Domenico
    Pala, Valeria
    Panico, Salvatore
    Tumino, Rosario
    Ricceri, Fulvio
    Bueno-de-Mesquita, H Bas
    Siersema, Peter D
    Peeters, Petra M
    Quiros, Jose Ramon
    Duell, Eric J
    Molina-Montes, Esther
    Chirlaque, Maria-Dolores
    Gurrea, Aurelio Barricarte
    Dorronsoro, Miren
    Lindkvist, Björn
    Johansen, Dorthe
    Werner, Mårten
    Sund, Malin
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J
    Travis, Ruth C
    Rinaldi, Sabina
    Romieu, Isabelle
    Gunter, Marc J
    Riboli, Elio
    Jenab, Mazda
    Kaaks, Rudolf
    Pre-diagnostic plasma testosterone, sex hormone binding globulin, IGF-I and hepatocellular carcinoma: etiological factors or risk markers?2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 1, p. 164-173Article in journal (Refereed)
    Abstract [en]

    Elevated pre-diagnostic testosterone and insulin-like growth factor-I (IGF-I) concentrations have been proposed to increase risk of hepatocellular carcinoma (HCC). However, the metabolism of these hormones is altered as a consequence of liver damage and they may have clinical utility as HCC risk markers. A case-control study was nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and included 125 incident HCC cases and 247 individually matched controls. Testosterone, sex hormone binding globulin (SHBG) and IGF-I were analyzed by immunoassays. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by conditional logistic regression. The area under the receiver operating curves (AUC) was calculated to assess HCC predictive ability of the tested models. After adjustments for epidemiological variables (body mass index, smoking, ethanol intake, hepatitis and diabetes) and liver damage (a score based on albumin, bilirubin, aspartate aminotransaminase, alanine aminotransaminase, gamma-glutamyltransferase and alkaline phosphatase concentrations), only SHBG remained significantly associated with risk (OR for top versus bottom tertile of 3.86 (1.32-11.3), ptrend =0.009). As a single factor SHBG had an AUC of 0.81 (0.75-0.86). A small, but significant increase in AUC was observed when SHBG was added to a model including the liver damage score and epidemiological variables (from 0.89 to 0.91, p=0.02) and a net reclassification of 0.47% (0.45-0.48). The observed associations of HCC with pre-diagnostic SHBG, free testosterone and IGF-I concentrations are in directions opposite to that expected under the etiological hypotheses. SHBG has a potential to be tested as pre-diagnostic risk marker for HCC.

  • 72. MacDonald, Brian A
    et al.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Grant, Marianne A
    Pfaff, Kathleen L
    Holthaus, Kathryn
    Zon, Leonard I
    Kalluri, Raghu
    Zebrafish to humans: evolution of the alpha3-chain of type IV collagen and emergence of the autoimmune epitopes associated with Goodpasture syndrome.2006In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 107, no 5, p. 1908-1915Article in journal (Refereed)
  • 73. Maggino, L.
    et al.
    Schmidt, A.
    Kaeding, A.
    Westermark, Sofia
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Gaujoux, S.
    Cystic Pancreatic Neuroendocrine Neoplasms: A Multicenter International Cohort Study2019In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 108, no Suppl. 1, p. 245-245Article in journal (Other academic)
    Abstract [en]

    Introduction: Natural history of cystic pancreatic neuroendocrine neoplasms (cPanNENs) is unknown, and their clinical management remains unclear. An observational strategy for asymptomatic cPanNENs ≤2cm has been proposed by recent guidelines, but evidence is scarce and limited to single-institutional series.

    Aim(s): Analyze a large international cohort of cPanNENs.

    Materials and methods: All resected cPanNENs (1995-2017) from 16 institutions worldwide were included. Solid lesions (>50% solid component), functional tumors and MEN-1 patients were excluded. Malignancy was defined as G3 grading, lymph node (LN) involvement, metastasis and/or recurrence.

    Results: Overall, 263 resected cPanNENs were included, among which 177 (63.5%) were preoperatively >2cm. A preoperative diagnosis of cPanNEN was established in 162 cases (61.6%) and was more frequent when patients underwent endoscopic ultrasound (EUS, OR 3.01, 95%CI 1.66-5.44) and nuclear medicine investigations (OR 3.97, 95%CI 1.93-8.18), and for those managed in high-volume institutions (OR 3.48, 95%CI 1.88-6.45). Forty-one cPanNENs (15.6%) were malignant. Suspicion of LN involvement on imaging, age >65 years, preoperative size >2cm and pancreatic duct dilation were independently associated with malignancy in the whole cohort. In asymptomatic patients, older age and a preoperative size >2cm remained independently associated with malignancy. Notably, malignancy occurred in only 1/61 asymptomatic patients with a preoperative size ≤2cm.

    Conclusion: The diagnostic accuracy of cPanNENs is increased by the use of EUS and nuclear medicine investigations and is higher in high-volume institutions. A preoperative size >2cm is independently associated with malignancy, so that a wait-and-see policy for sporadic asymptomatic cPanNENs≤ 2cm seems justified.

  • 74. McKenzie, Fiona
    et al.
    Ferrari, Pietro
    Freisling, Heinz
    Chajes, Veronique
    Rinaldi, Sabina
    de Batlle, Jordi
    Dahm, Christina C.
    Overvad, Kim
    Baglietto, Laura
    Dartois, Laureen
    Dossus, Laure
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Trichopoulou, Antonia
    Krogh, Vittorio
    Panico, Salvatore
    Tumino, Rosario
    Rosso, Stefano
    Bueno-de-Mesquita, H. B(As)
    May, Anne
    Peeters, Petra H.
    Weiderpass, Elisabete
    Buckland, Genevieve
    Sanchez, Maria-Jose
    Navarro, Carmen
    Ardanaz, Eva
    Andersson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ericson, Ulrika
    Wirfalt, Elisabet
    Key, Tim J.
    Travis, Ruth C.
    Gunter, Marc
    Riboli, Elio
    Vergnaud, Anne-Claire
    Romieu, Isabelle
    Healthy lifestyle and risk of breast cancer among postmenopausal women in the European Prospective Investigation into Cancer and Nutrition cohort study2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 11, p. 2640-2648Article in journal (Refereed)
    Abstract [en]

    Breast cancer is the most common cancer among women and prevention strategies are needed to reduce incidence worldwide. A healthy lifestyle index score (HLIS) was generated to investigate the joint effect of modifiable lifestyle factors on postmenopausal breast cancer risk. The study included 242,918 postmenopausal women from the multinational European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, with detailed information on diet and lifestyle assessed at baseline. The HLIS was constructed from five factors (diet, physical activity, smoking, alcohol consumption and anthropometry) by assigning scores of 0-4 to categories of each component, for which higher values indicate healthier behaviours. Hazard ratios (HR) were estimated by Cox proportional regression models. During 10.9 years of median follow-up, 7,756 incident breast cancer cases were identified. There was a 3% lower risk of breast cancer per point increase of the HLIS. Breast cancer risk was inversely associated with a high HLIS when fourth versus second (reference) categories were compared [adjusted HR=0.74; 95% confidence interval (CI): 0.66-0.83]. The fourth versus the second category of the HLIS was associated with a lower risk for hormone receptor double positive (adjusted HR=0.81, 95% CI: 0.67-0.98) and hormone receptor double negative breast cancer (adjusted HR=0.60, 95% CI: 0.40-0.90). Findings suggest having a high score on an index of combined healthy behaviours reduces the risk of developing breast cancer among postmenopausal women. Programmes which engage women in long term health behaviours should be supported. What's new? How much does behavior really affect cancer risk? These authors set out to measure just that. First, they created a Healthy Lifestyle Index, which quantified five modifiable behaviors, such as smoking and physical activity. Then, using data from the European Prospective Investigation into Cancer and Nutrition (EPIC), they assigned each participant a score between 0 and 4 on each of the behaviors. It turned out that with each point added to a person's Healthy Lifestyle Index score, breast cancer risk fell by 3%, suggesting that public programs to help women maintain these behaviors could be worthwhile for cancer prevention.

  • 75. Michailidou, Kyriaki
    et al.
    Beesley, Jonathan
    Lindstrom, Sara
    Canisius, Sander
    Dennis, Joe
    Lush, Michael J.
    Maranian, Mel J.
    Bolla, Manjeet K.
    Wang, Qin
    Shah, Mitul
    Perkins, Barbara J.
    Czene, Kamila
    Eriksson, Mikael
    Darabi, Hatef
    Brand, Judith S.
    Bojesen, Stig E.
    Nordestgaard, Borge G.
    Flyger, Henrik
    Nielsen, Sune F.
    Rahman, Nazneen
    Turnbull, Clare
    Fletcher, Olivia
    Peto, Julian
    Gibson, Lorna
    dos-Santos-Silva, Isabel
    Chang-Claude, Jenny
    Flesch-Janys, Dieter
    Rudolph, Anja
    Eilber, Ursula
    Behrens, Sabine
    Nevanlinna, Heli
    Muranen, Taru A.
    Aittomaki, Kristiina
    Blomqvist, Carl
    Khan, Sofia
    Aaltonen, Kirsimari
    Ahsan, Habibul
    Kibriya, Muhammad G.
    Whittemore, Alice S.
    John, Esther M.
    Malone, Kathleen E.
    Gammon, Marilie D.
    Santella, Regina M.
    Ursin, Giske
    Makalic, Enes
    Schmidt, Daniel F.
    Casey, Graham
    Hunter, David J.
    Gapstur, Susan M.
    Gaudet, Mia M.
    Diver, W. Ryan
    Haiman, Christopher A.
    Schumacher, Fredrick
    Henderson, Brian E.
    Le Marchand, Loic
    Berg, Christine D.
    Chanock, Stephen J.
    Figueroa, Jonine
    Hoover, Robert N.
    Lambrechts, Diether
    Neven, Patrick
    Wildiers, Hans
    van Limbergen, Erik
    Schmidt, Marjanka K.
    Broeks, Annegien
    Verhoef, Senno
    Cornelissen, Sten
    Couch, Fergus J.
    Olson, Janet E.
    Hallberg, Emily
    Vachon, Celine
    Waisfisz, Quinten
    Meijers-Heijboer, Hanne
    Adank, Muriel A.
    van der Luijt, Rob B.
    Li, Jingmei
    Liu, Jianjun
    Humphreys, Keith
    Kang, Daehee
    Choi, Ji-Yeob
    Park, Sue K.
    Yoo, Keun-Young
    Matsuo, Keitaro
    Ito, Hidemi
    Iwata, Hiroji
    Tajima, Kazuo
    Guenel, Pascal
    Truong, Therese
    Mulot, Claire
    Sanchez, Marie
    Burwinkel, Barbara
    Marme, Frederik
    Surowy, Harald
    Sohn, Christof
    Wu, Anna H.
    Tseng, Chiu-chen
    Van den Berg, David
    Stram, Daniel O.
    Gonzalez-Neira, Anna
    Benitez, Javier
    Zamora, M. Pilar
    Arias Perez, Jose Ignacio
    Shu, Xiao-Ou
    Lu, Wei
    Gao, Yu-Tang
    Cai, Hui
    Cox, Angela
    Cross, Simon S.
    Reed, Malcolm W. R.
    Andrulis, Irene L.
    Knight, Julia A.
    Glendon, Gord
    Mulligan, Anna Marie
    Sawyer, Elinor J.
    Tomlinson, Ian
    Kerin, Michael J.
    Miller, Nicola
    Lindblom, Annika
    Margolin, Sara
    Teo, Soo Hwang
    Yip, Cheng Har
    Taib, Nur Aishah Mohd
    Tan, Gie-Hooi
    Hooning, Maartje J.
    Hollestelle, Antoinette
    Martens, John W. M.
    Collee, J. Margriet
    Blot, William
    Signorello, Lisa B.
    Cai, Qiuyin
    Hopper, John L.
    Southey, Melissa C.
    Tsimiklis, Helen
    Apicella, Carmel
    Shen, Chen-Yang
    Hsiung, Chia-Ni
    Wu, Pei-Ei
    Hou, Ming-Feng
    Kristensen, Vessela N.
    Nord, Silje
    Alnaes, Grethe I. Grenaker
    Giles, Graham G.
    Milne, Roger L.
    McLean, Catriona
    Canzian, Federico
    Trichopoulos, Dimitrios
    Peeters, Petra
    Lund, Eiliv
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Khaw, Kay-Tee
    Gunter, Marc J.
    Palli, Domenico
    Mortensen, Lotte Maxild
    Dossus, Laure
    Huerta, Jose-Maria
    Meindl, Alfons
    Schmutzler, Rita K.
    Sutter, Christian
    Yang, Rongxi
    Muir, Kenneth
    Lophatananon, Artitaya
    Stewart-Brown, Sarah
    Siriwanarangsan, Pornthep
    Hartman, Mikael
    Miao, Hui
    Chia, Kee Seng
    Chan, Ching Wan
    Fasching, Peter A.
    Hein, Alexander
    Beckmann, Matthias W.
    Haeberle, Lothar
    Brenner, Hermann
    Dieffenbach, Aida Karina
    Arndt, Volker
    Stegmaier, Christa
    Ashworth, Alan
    Orr, Nick
    Schoemaker, Minouk J.
    Swerdlow, Anthony J.
    Brinton, Louise
    Garcia-Closas, Montserrat
    Zheng, Wei
    Halverson, Sandra L.
    Shrubsole, Martha
    Long, Jirong
    Goldberg, Mark S.
    Labreche, France
    Dumont, Martine
    Winqvist, Robert
    Pylkas, Katri
    Jukkola-Vuorinen, Arja
    Grip, Mervi
    Brauch, Hiltrud
    Hamann, Ute
    Bruening, Thomas
    Radice, Paolo
    Peterlongo, Paolo
    Manoukian, Siranoush
    Bernard, Loris
    Bogdanova, Natalia V.
    Doerk, Thilo
    Mannermaa, Arto
    Kataja, Vesa
    Kosma, Veli-Matti
    Hartikainen, Jaana M.
    Devilee, Peter
    Tollenaar, Robert A. E. M.
    Seynaeve, Caroline
    Van Asperen, Christi J.
    Jakubowska, Anna
    Lubinski, Jan
    Jaworska, Katarzyna
    Huzarski, Tomasz
    Sangrajrang, Suleeporn
    Gaborieau, Valerie
    Brennan, Paul
    Mckay, James
    Slager, Susan
    Toland, Amanda E.
    Ambrosone, Christine B.
    Yannoukakos, Drakoulis
    Kabisch, Maria
    Torres, Diana
    Neuhausen, Susan L.
    Anton-Culver, Hoda
    Luccarini, Craig
    Baynes, Caroline
    Ahmed, Shahana
    Healey, Catherine S.
    Tessier, Daniel C.
    Vincent, Daniel
    Bacot, Francois
    Pita, Guillermo
    Rosario Alonso, M.
    Alvarez, Nuria
    Herrero, Daniel
    Simard, Jacques
    Pharoah, Paul P. D. P.
    Kraft, Peter
    Dunning, Alison M.
    Chenevix-Trench, Georgia
    Hall, Per
    Easton, Douglas F.
    Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 4, p. 373-U127Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining similar to 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 x 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

  • 76. Michaud, Dominique S
    et al.
    Izard, Jacques
    Wilhelm-Benartzi, Charlotte S
    You, Doo-Ho
    Grote, Verena A
    Tjønneland, Anne
    Dahm, Christina C
    Overvad, Kim
    Jenab, Mazda
    Fedirko, Veronika
    Boutron-Ruault, Marie Christine
    Clavel-Chapelon, Françoise
    Racine, Antoine
    Kaaks, Rudolf
    Boeing, Heiner
    Foerster, Jana
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Sacerdote, Carlotta
    Sieri, Sabina
    Palli, Domenico
    Tumino, Rosario
    Panico, Salvatore
    Siersema, Peter D
    Peeters, Petra Hm
    Lund, Eiliv
    Barricarte, Aurelio
    Huerta, José-María
    Molina-Montes, Esther
    Dorronsoro, Miren
    Quirós, J Ramón
    Duell, Eric J
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lindkvist, Björn
    Johansen, Dorthe
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C
    Vineis, Paolo
    Bueno-de-Mesquita, H Bas
    Riboli, Elio
    Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study2013In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 62, no 12, p. 1764-1770Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Examine the relationship between antibodies to 25 oral bacteria and pancreatic cancer risk in a prospective cohort study. DESIGN: We measured antibodies to oral bacteria in prediagnosis blood samples from 405 pancreatic cancer cases and 416 matched controls, nested within the European Prospective Investigation into Cancer and Nutrition study. Analyses were conducted using conditional logistic regression and additionally adjusted for smoking status and body mass index. RESULTS: Individuals with high levels of antibodies against Porphyromonas gingivalis ATTC 53978, a pathogenic periodontal bacteria, had a twofold higher risk of pancreatic cancer than individuals with lower levels of these antibodies (OR 2.14; 95% CI 1.05 to 4.36; >200 ng/ml vs ≤200 ng/ml). To explore the association with commensal (non-pathogenic) oral bacteria, we performed a cluster analysis and identified two groups of individuals, based on their antibody profiles. A cluster with overall higher levels of antibodies had a 45% lower risk of pancreatic cancer than a cluster with overall lower levels of antibodies (OR 0.55; 95% CI 0.36 to 0.83). CONCLUSIONS: Periodontal disease might increase the risk for pancreatic cancer. Moreover, increased levels of antibodies against specific commensal oral bacteria, which can inhibit growth of pathogenic bacteria, might reduce the risk of pancreatic cancer. Studies are needed to determine whether oral bacteria have direct effects on pancreatic cancer pathogenesis or serve as markers of the immune response.

  • 77. Molina-Montes, Esther
    et al.
    Sanchez, Maria-Jose
    Buckland, Genevieve
    Bueno-de-Mesquita, H. B(as)
    Weiderpass, Elisabete
    Amiano, Pilar
    Wark, Petra A.
    Kuehn, Tilman
    Katzke, Verena
    Maria Huerta, Jose
    Ardanaz, Eva
    Ramon Quiros, Jose
    Affret, Aurelie
    His, Mathilde
    Boutron-Ruault, Marie-Christine
    Peeters, Petra H.
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Boeing, Heiner
    Iqbal, Khalid
    Ohlsson, Bodil
    Sonestedt, Emily
    Tjonneland, Anne
    Petersen, Kristina E. N.
    Travis, Ruth C.
    Skeie, Guri
    Agnoli, Claudia
    Panico, Salvatore
    Palli, Domenico
    Tumino, Rosario
    Sacerdote, Carlotta
    Freisling, Heinz
    Huybrechts, Inge
    Overvad, Kim
    Trichopoulou, Antonia
    Bamia, Christina
    Vasilopoulou, Effie
    Wareham, Nick
    Khaw, Kay-Tee
    Cross, Amanda J.
    Ward, Heather A.
    Riboli, Elio
    Duell, Eric J.
    Mediterranean diet and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition cohort2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 116, no 6, p. 811-820Article in journal (Refereed)
    Abstract [en]

    Background: The Mediterranean diet (MD) has been proposed as a means for cancer prevention, but little evidence has been accrued regarding its potential to prevent pancreatic cancer. We investigated the association between the adherence to the MD and pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

    Methods: Over half a million participants from 10 European countries were followed up for over 11 years, after which 865 newly diagnosed exocrine pancreatic cancer cases were identified. Adherence to the MD was estimated through an adapted score without the alcohol component (arMED) to discount alcohol-related harmful effects. Cox proportional hazards regression models, stratified by age, sex and centre, and adjusted for energy intake, body mass index, smoking status, alcohol intake and diabetes status at recruitment, were used to estimate hazard ratios (HRs) associated with pancreatic cancer and their corresponding 95% confidence intervals (CIs).

    Results: Adherence to the arMED score was not associated with risk of pancreatic cancer (HR highvs low adherence=0.99; 95% CI: 0.77–1.26, and HR per increments of two units in adherence to arMED=1.00; 95% CI: 0.94–1.06). There was no convincing evidence for heterogeneity by smoking status, body mass index, diabetes or European region. There was also no evidence of significant associations in analyses involving microscopically confirmed cases, plausible reporters of energy intake or other definitions of the MD pattern.

    Conclusions: A high adherence to the MD is not associated with pancreatic cancer risk in the EPIC study.

  • 78. Molina-Montes, Esther
    et al.
    Sanchez, Maria-Jose
    Zamora-Ros, Raul
    Bueno-de-Mesquita, H. B(as)
    Wark, Petra A.
    Obon-Santacana, Mireia
    Kuehn, Tilman
    Katzke, Verena
    Travis, Ruth C.
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Naccarati, Alessio
    Mattiello, Amalia
    Krogh, Vittorio
    Martorana, Caterina
    Masala, Giovanna
    Amiano, Pilar
    Huerta, Jose-Maria
    Barricarte, Aurelio
    Quiros, Jose-Ramon
    Weiderpass, Elisabete
    Asli, Lene Angell
    Skeie, Guri
    Ericson, Ulrika
    Sonestedt, Emily
    Peeters, Petra H.
    Romieu, Isabelle
    Scalbert, Augustin
    Overvad, Kim
    Clemens, Matthias
    Boeing, Heiner
    Trichopoulou, Antonia
    Peppa, Eleni
    Vidalis, Pavlos
    Khaw, Kay-Tee
    Wareham, Nick
    Olsen, Anja
    Tjonneland, Anne
    Boutroun-Rualt, Marie-Christine
    Clavel-Chapelon, Francoise
    Cross, Amanda J.
    Lu, Yunxia
    Riboli, Elio
    Duell, Eric J.
    Flavonoid and lignan intake and pancreatic cancer risk in the European prospective investigation into cancer and nutrition cohort2016In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 139, no 7, p. 1480-1492Article in journal (Refereed)
    Abstract [en]

    Despite the potential cancer preventive effects of flavonoids and lignans, their ability to reduce pancreatic cancer risk has not been demonstrated in epidemiological studies. Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 865 exocrine pancreatic cancer cases occurred after 11.3 years of follow-up of 477,309 cohort members. Dietary flavonoid and lignan intake was estimated through validated dietary questionnaires and the US Department of Agriculture (USDA) and Phenol Explorer databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using age, sex and center-stratified Cox proportional hazards models, adjusted for energy intake, body mass index (BMI), smoking, alcohol and diabetes status. Our results showed that neither overall dietary intake of flavonoids nor of lignans were associated with pancreatic cancer risk (multivariable-adjusted HR for a doubling of intake=1.03, 95% CI: 0.95-1.11 and 1.02; 95% CI: 0.89-1.17, respectively). Statistically significant associations were also not observed by flavonoid subclasses. An inverse association between intake of flavanones and pancreatic cancer risk was apparent, without reaching statistical significance, in microscopically confirmed cases (HR for a doubling of intake=0.96, 95% CI: 0.91-1.00). In conclusion, we did not observe an association between intake of flavonoids, flavonoid subclasses or lignans and pancreatic cancer risk in the EPIC cohort. What's new? Flavonoids and lignans found in plant-based foods are potent cancer chemopreventive agents but little is known about their effects on pancreatic cancer risk. Here the authors address this question in a large prospective epidemiological study using comprehensively derived dietary data. Their results support growing evidence that there is no association between food-based consumption of both substances with pancreatic cancer risk.

  • 79. Molina-Montes, Esther
    et al.
    Wark, Petra A
    Sánchez, María-José
    Norat, Teresa
    Jakszyn, Paula
    Luján-Barroso, Leila
    Michaud, Dominique S
    Crowe, Francesca
    Allen, Naomi
    Khaw, Kay-Tee
    Wareham, Nicholas
    Trichopoulou, Antonia
    Adarakis, George
    Katarachia, Helen
    Skeie, Guri
    Henningsen, Maria
    Broderstad, Ann Ragnhild
    Berrino, Franco
    Tumino, Rosario
    Palli, Domenico
    Mattiello, Amalia
    Vineis, Paolo
    Amiano, Pilar
    Barricarte, Aurelio
    Huerta, José-María
    Duell, Eric J
    Quirós, José-Ramón
    Ye, Weimin
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lindkvist, Björn
    Johansen, Dorthe
    Overvad, Kim
    Tjønneland, Anne
    Roswall, Nina
    Li, Kuanrong
    Grote, Verena A
    Steffen, Annika
    Boeing, Heiner
    Racine, Antoine
    Boutron-Ruault, Marie-Christine
    Carbonnel, Franck
    Peeters, Petra Hm
    Siersema, Peter D
    Fedirko, Veronika
    Jenab, Mazda
    Riboli, Elio
    Bueno-de-Mesquita, Bas
    Dietary intake of iron, heme-iron and magnesium and pancreatic cancer risk in the European prospective investigation into cancer and nutrition cohort.2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, no 7, p. E1134-E1147Article in journal (Refereed)
    Abstract [en]

    Several studies support a protective effect of dietary magnesium against type 2 diabetes, but a harmful effect for iron. As diabetes has been linked to pancreatic cancer, intake of these nutrients may be also associated with this cancer. We examined the association between dietary intake of magnesium, total iron and heme-iron and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. In total, 142,203 men and 334,999 women, recruited between 1992 and 2000, were included. After an average follow-up of 11.3 years, 396 men and 469 women developed exocrine pancreatic cancer. Hazard ratios and 95% confidence intervals (CIs) were obtained using Cox regression stratified by age and center, and adjusted for energy intake, smoking status, height, weight, and self-reported diabetes status. Neither intake of magnesium, total iron nor heme-iron was associated with pancreatic cancer risk. In stratified analyses, a borderline inverse association was observed among overweight men (body mass index, ≥25 kg/m(2) ) with magnesium (HR(per 100 mg/day increase) = 0.79, 95% CI = 0.63-1.01) although this was less apparent using calibrated intake. In female smokers, a higher intake of heme-iron was associated with a higher pancreatic cancer risk (HR (per 1 mg/day increase) = 1.38, 95% CI = 1.10-1.74). After calibration, this risk increased significantly to 2.5-fold (95% CI = 1.22-5.28). Overall, dietary magnesium, total iron and heme-iron were not associated with pancreatic cancer risk during the follow-up period. Our observation that heme-iron was associated with increased pancreatic cancer risk in female smokers warrants replication in additional study populations.

  • 80. Mondul, Alison M.
    et al.
    Shui, Irene M.
    Yu, Kai
    Weinstein, Stephanie J.
    Tsilidis, Konstantinos K.
    Joshi, Amit D.
    Agudo, Antonio
    Berg, Christine D.
    Black, Amanda
    Buring, Julie E.
    Chasman, Daniel I.
    Gaudet, Mia M.
    Haiman, Christopher
    Hankinson, Susan E.
    Henderson, Brian E.
    Hoover, Robert N.
    Hunter, David J.
    Khaw, Kay-Tee
    Kuehn, Tilman
    Kvaskoff, Marina
    Le Marchand, Loic
    Lindstroem, Sara
    McCullough, Marjorie L.
    Overvad, Kim
    Peeters, Petra H.
    Riboli, Elio
    Ridker, Paul M.
    Stram, Daniel O.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Trichopoulos, Dimitrios
    Tumino, Rosario
    Weiderpass, Elisabete
    Willett, Walter
    Kraft, Peter
    Ziegler, Regina G.
    Albanes, Demetrius
    Vitamin D-Associated Genetic Variation and Risk of Breast Cancer in the Breast and Prostate Cancer Cohort Consortium (BPC3)2015In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, no 3, p. 627-630Article in journal (Refereed)
    Abstract [en]

    Background: Two recent genome-wide association studies (GWAS) identified SNPs in or near four genes related to circulating 25-hydroxyvitamin D [25(OH) D] concentration. To examine the hypothesized inverse relationship between vitamin D status and breast cancer, we studied the associations between SNPs in these genes and breast cancer risk in a large pooled study of 9,456 cases and 10,816 controls from six cohorts. Methods: SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25 (OH) D were genotyped and examined both individually and as a 4-SNP polygenic score. Logistic regression was used to estimate the associations between the genetic variants and risk of breast cancer. Results: We found no association between any of the four SNPs or their polygenic score and breast cancer risk. Conclusions: Our findings do not support an association between vitamin D status, as reflected by 25(OH) D-related genotypes, and breast cancer risk. Impact: These findings may contribute to future meta-analyses and scientific review articles, and provide new data about the association between vitamin D-related genes and breast cancer.

  • 81. Morin, Eric
    et al.
    Sjöberg, Elin
    Tjomsland, Vegard
    Testini, Chiara
    Lindskog, Cecilia
    Franklin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Wallenberg Centre for Molecular Medicine, Umeå, Sweden.
    Kiflemariam, Sara
    Sjöblom, Tobias
    Claesson-Welsh, Lena
    VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival2018In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, no 3, p. 311-322Article in journal (Refereed)
    Abstract [en]

    Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival. 

  • 82. Muller, David C.
    et al.
    Murphy, Neil
    Johansson, Mattias
    Ferrari, Pietro
    Tsilidis, Konstantinos K.
    Boutron-Ruault, Marie-Christine
    Clavel, Francoise
    Dartois, Laureen
    Li, Kuanrong
    Kaaks, Rudolf
    Weikert, Cornelia
    Bergmann, Manuela
    Boeing, Heiner
    Tjonneland, Anne
    Overvad, Kim
    Luisa Redondo, M.
    Agudo, Antonio
    Molina-Portillo, Elena
    Altzibar, Jone M.
    Cirera, Lluis
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nicholas J.
    Key, Timothy J.
    Travis, Ruth C.
    Bamia, Christina
    Orfanos, Philippos
    Trichopoulou, Antonia
    Palli, Domenico
    Pala, Valeria
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Bueno-de-Mesquita, H. Bas
    Verschuren, W. M. Monique
    Struijk, Ellen A.
    Peeters, Petra H.
    Engstrom, Gunnar
    Melander, Olle
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Weiderpass, Elisabete
    Skeie, Guri
    Lund, Eiliv
    Norat, Teresa
    Gunter, Marc
    Riboli, Elio
    Brennan, Paul
    Modifiable causes of premature death in middle-age in Western Europe: results from the EPIC cohort study2016In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 14, article id 87Article in journal (Refereed)
    Abstract [en]

    Background: Life expectancy is increasing in Europe, yet a substantial proportion of adults still die prematurely before the age of 70 years. We sought to estimate the joint and relative contributions of tobacco smoking, hypertension, obesity, physical inactivity, alcohol and poor diet towards risk of premature death. Methods: We analysed data from 264,906 European adults from the EPIC prospective cohort study, aged between 40 and 70 years at the time of recruitment. Flexible parametric survival models were used to model risk of death conditional on risk factors, and survival functions and attributable fractions (AF) for deaths prior to age 70 years were calculated based on the fitted models. Results: We identified 11,930 deaths which occurred before the age of 70. The AF for premature mortality for smoking was 31 % (95 % confidence interval (CI), 31-32 %) and 14 % (95 % CI, 12-16 %) for poor diet. Important contributions were also observed for overweight and obesity measured by waist-hip ratio (10 %; 95 % CI, 8-12 %) and high blood pressure (9 %; 95 % CI, 7-11 %). AFs for physical inactivity and excessive alcohol intake were 7 % and 4 %, respectively. Collectively, the AF for all six risk factors was 57 % (95 % CI, 55-59 %), being 35 % (95 % CI, 32-37 %) among never smokers and 74 % (95 % CI, 73-75 %) among current smokers. Conclusions: While smoking remains the predominant risk factor for premature death in Europe, poor diet, overweight and obesity, hypertension, physical inactivity, and excessive alcohol consumption also contribute substantially. Any attempt to minimise premature deaths will ultimately require all six factors to be addressed.

  • 83. Naudin, Sabine
    et al.
    Li, Kuanrong
    Jaouen, Tristan
    Assi, Nada
    Kyrø, Cecilie
    Tjønneland, Anne
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Rebours, Vinciane
    Védié, Anne-Laure
    Boeing, Heiner
    Kaaks, Rudolf
    Katzke, Verena
    Bamia, Christina
    Naska, Androniki
    Trichopoulou, Antonia
    Berrino, Franco
    Tagliabue, Giovanna
    Palli, Domenico
    Panico, Salvatore
    Tumino, Rosario
    Sacerdote, Carlotta
    Peeters, Petra H
    Bueno-de-Mesquita, Bas
    Weiderpass Vainio, Elisabete
    Gram, Inger Torhild
    Skeie, Guri
    Chirlaque, Maria-Dolores
    Rodríguez-Barranco, Miguel
    Barricarte, Aurelio
    Quirós, Jose Ramón
    Dorronsoro, Miren
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sternby, Hanna
    Bradbury, Kathryn E
    Wareham, Nick
    Riboli, Elio
    Gunter, Marc
    Brennan, Paul
    Duell, Eric J
    Ferrari, Pietro
    Lifetime and baseline alcohol intakes and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition study2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 4, p. 801-812Article in journal (Refereed)
    Abstract [en]

    Recent evidence suggested a weak relationship between alcohol consumption and pancreatic cancer (PC) risk. In our study, the association between lifetime and baseline alcohol intakes and the risk of PC was evaluated, including the type of alcoholic beverages and potential interaction with smoking. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 1,283 incident PC (57% women) were diagnosed from 476,106 cancer-free participants, followed up for 14 years. Amounts of lifetime and baseline alcohol were estimated through lifestyle and dietary questionnaires, respectively. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and their 95% confidence interval (CI). Alcohol intake was positively associated with PC risk in men. Associations were mainly driven by extreme alcohol levels, with HRs comparing heavy drinkers (>60 g/day) to the reference category (0.1-4.9 g/day) equal to 1.77 (95% CI: 1.06, 2.95) and 1.63 (95% CI: 1.16, 2.29) for lifetime and baseline alcohol, respectively. Baseline alcohol intakes from beer (>40 g/day) and spirits/liquors (>10 g/day) showed HRs equal to 1.58 (95% CI: 1.07, 2.34) and 1.41 (95% CI: 1.03, 1.94), respectively, compared to the reference category (0.1-2.9 g/day). In women, HR estimates did not reach statistically significance. The alcohol and PC risk association was not modified by smoking status. Findings from a large prospective study suggest that baseline and lifetime alcohol intakes were positively associated with PC risk, with more apparent risk estimates for beer and spirits/liquors than wine intake.

  • 84. Nichols, Hazel B.
    et al.
    Schoemaker, Minouk J.
    Cai, Jianwen
    Xu, Jiawei
    Wright, Lauren B.
    Brook, Mark N.
    Jones, Michael E.
    Adami, Hans-Olov
    Baglietto, Laura
    Bertrand, Kimberly A.
    Blot, William J.
    Boutron-Ruault, Marie-Christine
    Dorronsoro, Miren
    Dossus, Laure
    Eliassen, A. Heather
    Giles, Graham G.
    Gram, Inger T.
    Hankinson, Susan E.
    Hoffman-Bolton, Judy
    Kaaks, Rudolf
    Key, Timothy J.
    Kitahara, Cari M.
    Larsson, Susanna C.
    Linet, Martha
    Merritt, Melissa A.
    Milne, Roger L.
    Pala, Valeria
    Palmer, Julie R.
    Peeters, Petra H.
    Riboli, Elio
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Tamimi, Rulla M.
    Tjønneland, Anne
    Trichopoulou, Antonia
    Ursin, Giske
    Vatten, Lars
    Visvanathan, Kala
    Weiderpass, Elisabete
    Wolk, Alicja
    Zheng, Wei
    Weinberg, Clarice R.
    Swerdlow, Anthony J.
    Sandler, Dale P.
    Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies2019In: Annals of Internal Medicine, ISSN 0003-4819, E-ISSN 1539-3704, Vol. 170, no 1, p. 22-30Article in journal (Refereed)
    Abstract [en]

    Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated.

    Objective: To characterize breast cancer risk in relation to recent childbirth.

    Design: Pooled analysis of individual-level data from 15 prospective cohort studies.

    Setting: The international Premenopausal Breast Cancer Collaborative Group.

    Participants: Women younger than 55 years.

    Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression.

    Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns.

    Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited.

    Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women.

    Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

  • 85. Nichols, Hazel B.
    et al.
    Schoemaker, Minouk J.
    Wright, Lauren B.
    McGowan, Craig
    Brook, Mark N.
    McClain, Kathleen M.
    Jones, Michael E.
    Adami, Hans-Olov
    Agnoli, Claudia
    Baglietto, Laura
    Bernstein, Leslie
    Bertrand, Kimberly A.
    Blots, William J.
    Boutron-Ruaults, Marie-Christine
    Butler, Lesley
    Chenl, Yu
    Doody, Michele M.
    Dossus, Laure
    Eliassen, A. Heather
    Giles, Graham G.
    Gram, Inger T.
    Hankinson, Susan E.
    Hoffman-Bolton, Judy
    Kaaks, Rudolf
    Key, Timothy J.
    Kirsh, Victoria A.
    Kitahara, Can M.
    Koh, Woon-Puay
    Larsson, Susanna C.
    Lund, Eiliv
    Ma, Huiyan
    Merritt, Melissa A.
    Milne, Roger L.
    Navarro, Carmen
    Overvad, Kim
    Ozasa, Kotaro
    Palmer, Julie R.
    Peeters, Petra H.
    Riboli, Elio
    Rohan, Thomas E.
    Sadakane, Atsuko
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Tamimi, Rulla M.
    Trichopoulou, Antonia
    Vatten, Lars
    Visvanathan, Kala
    Weiderpass, Elisabete
    Willett, Walter C.
    Wolk, Alicja
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Sandler, Dale P.
    Swerdlow, Anthony J.
    The Premenopausal Breast Cancer Collaboration: A Pooling Project of Studies Participating in the National Cancer Institute Cohort Consortium2017In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 26, no 9, p. 1360-1369Article, review/survey (Refereed)
    Abstract [en]

    Breast cancer is a leading cancer diagnosis among premenopausal women around the world. Unlike rates in postmenopausal women, incidence rates of advanced breast cancer have increased in recent decades for premenopausal women. Progress in identifying contributors to breast cancer risk among premenopausal women has been constrained by the limited numbers of premenopausal breast cancer cases in individual studies and resulting low statistical power to subcategorize exposures or to study specific subtypes. The Premenopausal Breast Cancer Collaborative Group was established to facilitate cohort-based analyses of risk factors for premenopausal breast cancer by pooling individuallevel data from studies participating in the United States National Cancer Institute Cohort Consortium. This article describes the Group, including the rationale for its initial aims related to pregnancy, obesity, and physical activity. We also describe the 20 cohort studies with data submitted to the Group by June 2016. The infrastructure developed for this work can be leveraged to support additional investigations.

  • 86. Nilchian, Azadeh
    et al.
    Johansson, Joel
    Ghalali, Aram
    Travica Asanin, Sandra
    Santiago, Ana
    Rosencrantz, Oskar
    Vincent, C Theresa
    Sollerbrant, Kerstin
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Stenius, Ulla
    Fuxe, Jonas
    CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer.2019In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 1, p. 47-60Article in journal (Refereed)
    Abstract [en]

    Tight junctions (TJ) act as hubs for intracellular signaling pathways controlling epithelial cell fate and function. Deregulation of TJ is a hallmark of epithelial-mesenchymal transition (EMT), which contributes to carcinoma progression and metastasis. However, the signaling mechanisms linking TJ to the induction of EMT are not understood. Here we identify a TJ-based signalosome, which controls AKT signaling and EMT in breast cancer. The coxsackie- and adenovirus receptor (CXADR), a TJ protein with an essential yet uncharacterized role in organogenesis and tissue homeostasis, was identified as a key component of the signalosome. CXADR regulated the stability and function of the phosphatases and AKT inhibitors PTEN and PHLPP2. Loss of CXADR led to hyper-activation of AKT and sensitized cells to TGF-β1-induced EMT. Conversely, restoration of CXADR stabilized PHLPP2 and PTEN, inhibited AKT, and promoted epithelial differentiation. Loss of CXADR in luminal A breast cancer correlated with loss of PHLPP2 and PTEN and poor prognosis. These results show that CXADR promotes the formation of an AKT-inhibitory signalosome at TJ and regulates epithelial-mesenchymal plasticity in breast cancer cells. Moreover, loss of CXADR might be used as a prognostic marker in luminal breast cancer.

  • 87. Nyberg, Pia
    et al.
    Xie, Liang
    Sugimoto, Hikaru
    Colorado, Pablo
    Sund, Malin
    Holthaus, Kathryn
    Sudhakar, Akulapalli
    Salo, Tuula
    Kalluri, Raghu
    Characterization of the anti-angiogenic properties of arresten, an alpha1beta1 integrin-dependent collagen-derived tumor suppressor2008In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 314, no 18, p. 3292-3305Article in journal (Refereed)
    Abstract [en]

    Physiological and pathological turnover of basement membranes liberates biologically active cryptic molecules. Several collagen-derived fragments possess anti-angiogenic activity. Arresten is the 26-kDa non-collagenous domain of type IV collagen alpha1 chain. It functions as an efficient inhibitor of angiogenesis and tumor growth in mouse models, but its anti-angiogenic mechanism is not completely known. Here we show that arresten significantly increases apoptosis of endothelial cells in vitro by decreasing the amount of anti-apoptotic molecules of the Bcl-family; Bcl-2 and Bcl-xL. Although the pro-apoptotic effect of arresten is endothelial cell specific in vitro, in mouse tumors arresten induced apoptosis both in endothelial and tumor cells. The tumor cell apoptosis is likely an indirect effect due to the inhibition of blood vessel growth into the tumor. The active site of arresten was localized by deletion mutagenesis within the C-terminal half of the molecule. We have previously shown that arresten binds to alpha1beta1 integrin on human umbilical vein endothelial cells. However, the microvascular endothelial cells (MLECs) are more important in the context of tumor vasculature. We show here that arresten binds also to the microvascular endothelial cells via alpha1beta1 integrin. Furthermore, it has no effect on Matrigel neovascularization or the viability of integrin alpha1 null MLECs. Tumors implanted on integrin alpha1 deficient mice show no integrin alpha1 expression in the host-derived vascular endothelium, and thus arresten does not inhibit the tumor growth. Collectively, this data sheds more light into the anti-angiogenic mechanism of arresten.

  • 88.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Björklund, Moa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nygren, Pia
    Department of Diagnosics and Oral Medicine, University of Oulu, Finland.
    Saalo, Tula
    Department of Diagnostics and Oral Medicine, University of Oulu, Finland.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Increased type IV collagen expression is a feature in liver metastases of epithelial origin and related to invasiveness of CRC cells in a novel organotypic liver metastatic modelArticle in journal (Other academic)
  • 89.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Berglund, Anette
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Liver-metastatic potential of colorectal cancer is related to the stromal composition of the tumour2012In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 12, p. 5183-5191Article in journal (Refereed)
    Abstract [en]

    Background: The tumour stroma is an important modulator of cancer cell behaviour. The aim of this study was to compare the stromal composition between primary colorectal cancer (CRC) and colorectal liver metastases (CLM).

    Materials and Methods: The stromal composition in matched tissue sections of CRC and subsequent CLM was analysed, and related to clinical parameters.

    Results: Differences in the expression pattern of type I collagen and type IV collagen in CRC was related to a higher risk of CLM. Two types of CLM the desmoplastic and pushing type were identified. The time between CRC and diagnosis of CLM was shorter (p=0.047) for desmoplastic CLM. The mortality rate was higher for pushing CLM due to frequent extrahepatic disseminated disease. A difference in the overall survival rate between patients with desmoplastic and those with pushing CLM was seen at follow-up of more than 60 months (p=0.046).

    Conclusion: The liver-metastasizing potential is related to the stromal composition of primary CRC. There are distinct growth patterns in CLM with differences in stromal composition and clinical outcome.

  • 90.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hafström, Larsolof
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Type IV collagen as a tumour marker for colorectal liver metastases2011In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 37, no 7, p. 611-617Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: About 50% of patients with primary colorectal cancer (CRC) will develop liver metastases (CLM). Currently, carcinoembryonic antigen (CEA) is the most common tumour marker for CRC and CLM. However, the sensitivity and specificity of this marker is not optimal, as almost 50% of patients have tumours that do not produce CEA. Therefore there is a need for better markers for CRC and CLM.

    METHODS: The circulating levels of type IV collagen were measured in patients with CLM, primary CRC and in healthy controls. The expression pattern of type IV collagen was studied by immunofluorescence in CLM and normal liver tissue. The metastatic volume of CLM in the liver was estimated from CT.

    RESULTS: In CLM tissue type IV collagen is highly expressed in the areas of desmoplasia. Patients with primary CRC (Dukes' A-C) did not show any increase in circulating type IV collagen compared to healthy controls. However, patients with CLM have significantly elevated levels of circulating type IV collagen when compared to patients with primary CRC and healthy controls. The levels of type IV collagen decreased during chemotherapy and increased at the time of disease progression. The circulating levels of type IV collagen seem to reflect the tumour burden in the liver.

    CONCLUSIONS: Type IV collagen has the potential to be used as tumour associated biomarker for CLM. These results indicate the importance of interaction between cancer cells and the stroma in the tumour microenvironment.

  • 91.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Björklund, Moa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Improved tumor marker sensitivity by combined type IV collagen and CEA measurement in colorectal liver metastasesArticle in journal (Other academic)
  • 92.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Björklund, Moa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Improved tumour marker sensitivity in detecting colorectal liver metastases by combined type IV collagen and CEA measurement2015In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 36, no 12, p. 9839-9847Article in journal (Refereed)
    Abstract [en]

    Carcinoembryonic antigen (CEA) is the best circulating tumour marker for colorectal liver metastasis (CLM) but has suboptimal sensitivity and specificity. Circulating type IV collagen (COLIV) is a new potential CLM marker. Here, COLIV and CEA were measured in patients with resectable CLM. COLIV levels were also related to the type of CLM. The prognostic value of these markers and the type of CLM on survival was evaluated. Preoperative plasma samples (n = 94) from patients (n = 85) with CLM undergoing liver resection were used. Seven patients underwent repeated liver resection. Samples from 118 healthy individuals served as control. Samples after liver resection (n = 27) were analysed and related to recurrence. COLIV and CEA levels were analysed, and the type of CLM was classified using paraffinated tissue. Results were analysed by logistic regression and receiver operating characteristic (ROC) curve analysis. CLM patients had significantly elevated levels of COLIV compared to controls (p = 0.001). The sensitivity of COLIV was not better than CEA, but improved sensitivity for detecting CLM was observed with a combination of the two markers compared to using either marker alone (p = 0.001). Circulating COLIV was elevated in 81 % and CEA in 56 % of CLM patients at diagnosis, and high marker levels were related to poor survival. In follow-up samples (n = 27), patients with CLM recurrence (n = 14) had significantly elevated COLIV levels compared to patients without postoperative recurrence (n = 10) (p = 0.001). COLIV is a promising tumour marker for CLM and can possibly be used to detect postoperative CLM recurrence. The combination of COLIV and CEA is superior to either marker alone in detecting CLM.

  • 93. Obón-Santacana, M.
    et al.
    Slimani, N.
    Lujan-Barroso, L.
    Travier, N.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Freisling, H.
    Ferrari, P.
    Boutron-Ruault, M. C.
    Racine, A.
    Clavel, F.
    Saieva, C.
    Pala, V.
    Tumino, R.
    Mattiello, A.
    Vineis, P.
    Argüelles, M.
    Ardanaz, E.
    Amiano, P.
    Navarro, C.
    Sánchez, M. J.
    Molina Montes, E.
    Key, T.
    Khaw, K.-T.
    Wareham, N.
    Peeters, P. H.
    Trichopoulou, A.
    Bamia, C.
    Trichopoulos, D.
    Boeing, H..
    Kaaks, R
    Katzke, V.
    Ye, W.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ericson, U.
    Wirfält, E..
    Overvad, K.
    Tjønneland, A.
    Olsen, A.
    Skeie, G.
    Asli, L. A.
    Weiderpass, E.
    Riboli, E.
    Bueno-de-Mesquita, H. B.
    Duell, EJ
    Dietary intake of acrylamide and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2013In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, no 10, p. 2645-2651Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In 1994, acrylamide (AA) was classified as a probable human carcinogen by the International Agency for Research on Cancer. In 2002, AA was discovered at relatively high concentrations in some starchy, plant-based foods cooked at high temperatures.

    PATIENTS AND METHODS: A prospective analysis was conducted to evaluate the association between the dietary intake of AA and ductal adenocarcinoma of the exocrine pancreatic cancer (PC) risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort using Cox regression modeling. EPIC includes >500 000 men and women aged 35-75 at enrollment from 10 European countries. AA intake was estimated for each participant by combining questionnaire-based food consumption data with a harmonized AA database derived from the EU monitoring database of AA levels in foods, and evaluated in quintiles and continuously.

    RESULTS: After a mean follow-up of 11 years, 865 first incident adenocarcinomas of the exocrine pancreas were observed and included in the present analysis. At baseline, the mean dietary AA intake in EPIC was 26.22 µg/day. No overall association was found between continuous or quintiles of dietary AA intake and PC risk in EPIC (HR:0.95, 95%CI:0.89-1.01 per 10 µg/day). There was no effect measure modification by smoking status, sex, diabetes, alcohol intake or geographic region. However, there was an inverse association (HR: 0.73, 95% CI: 0.61-0.88 per 10 µg/day) between AA intake and PC risk in obese persons as defined using the body mass index (BMI, ≥30 kg/m(2)), but not when body fatness was defined using waist and hip circumference or their ratio.

    CONCLUSIONS: Dietary intake of AA was not associated with an increased risk of PC in the EPIC cohort.

  • 94. Pang, M-F
    et al.
    Georgoudaki, A-M
    Lambut, L.
    Johansson, J.
    Tabor, V.
    Hagikura, K.
    Jin, Y.
    Jansson, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Alexander, J. S.
    Nelson, C. M.
    Jakobsson, L.
    Betsholtz, C.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Karlsson, M. C. I.
    Fuxe, J.
    TGF-beta 1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis2016In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, no 6, p. 748-760Article in journal (Refereed)
    Abstract [en]

    Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial-mesenchymal transition (EMT) in response to transforming growth factor-beta (TGF-beta 1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-beta 1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-beta 1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-beta 1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-beta 1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.

  • 95.
    Plaks, Vicki
    et al.
    Department of Anatomy, University of California, San Francisco, CA 94143.
    Rinkenberger, Julie
    Department of Anatomy, University of California, San Francisco, CA 94143.
    Dai, Joanne
    Department of Anatomy, University of California, San Francisco, CA 94143.
    Flannery, Margaret
    Department of Anatomy, University of California, San Francisco, CA 94143.
    Sund, Malin
    Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
    Kanasaki, Keizo
    Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
    Ni, Wei
    Department of Medicine and Diabetes Center, University of California, San Francisco, CA 94143.
    Kalluri, Raghu
    Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
    Werb, Zena
    Department of Anatomy, University of California, San Francisco, CA 94143.
    Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 27, p. 11109-11114Article in journal (Refereed)
    Abstract [en]

    The pregnancy complication preeclampsia (PE), which occurs in approximately 3% to 8% of human pregnancies, is characterized by placental pathologies that can lead to significant fetal and maternal morbidity and mortality. Currently, the only known cure is delivery of the placenta. As the etiology of PE remains unknown, it is vital to find models to study this common syndrome. Here we show that matrix metalloproteinase-9 (MMP9) deficiency causes physiological and placental abnormalities in mice, which mimic features of PE. As with the severe cases of this syndrome, which commence early in gestation, MMP9-null mouse embryos exhibit deficiencies in trophoblast differentiation and invasion shortly after implantation, along with intrauterine growth restriction or embryonic death. Reciprocal embryo transfer experiments demonstrated that embryonic MMP9 is a major contributor to normal implantation, but maternal MMP9 also plays a role in embryonic trophoblast development. Pregnant MMP9-null mice bearing null embryos exhibited clinical features of PE as VEGF dysregulation and proteinuria accompanied by preexisting elevated blood pressure and kidney pathology. Thus, our data show that fetal and maternal MMP9 play a role in the development of PE and establish the MMP9-null mice as a much-needed model to study the clinical course of this syndrome.

  • 96.
    Ramazani, Mari
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Increased circulating levels of basement-membrane components in patients with abdominal aortic aneurysms: A Pilot Study2011In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 42, no 4, p. 484-487Article in journal (Refereed)
    Abstract [en]

    Aim: The decision for abdominal aortic aneurysm (AM) repair is based on aneurysm size. However, smaller aneurysms can rupture, while larger ones can remain stable. New variables and markers are needed to better select patients at high rupture risk. The study was done to analyse if AAA patients have increased levels of circulating basement-membrane (BM) fragments.

    Design: Circulating levels of BM components type IV and XVIII collagen were measured by enzyme-linked immunosorbent assay (ELISA) in 10 patients with AAA, nine patients with peripheral artery disease (PAD) and 10 healthy controls (CON).

    Results: AAA patients had significantly increased levels of type IV and XVIII collagen compared with CON (134.0 +/- 24.8 ng ml(-1) vs. 104.5 +/- 16.4 ng ml(-1); p = 0.005 and 149.0 +/- 56.9 ng ml(-1) vs. 59.6 +/- 8.7 ng ml(-1); p < 0.001, respectively). The PAD patients did not have significantly increased levels of these fragments when compared with CON. In addition, the AAA patients had significantly increased level of type XVIII collagen (149.0 +/- 56.9 ng ml(-1) vs. 58.3 +/- 25.4 ng/ml(-1); p < 0.01) when compared with the PAD group.

    Conclusion: Based on this preliminary analysis of a small number of subjects, patients with AAA had significantly increased levels of circulating BM components. BM fragments should be studied further to establish their potential role as biomarkers for AAA.

  • 97. Ricceri, Fulvio
    et al.
    Fasanelli, Francesca
    Giraudo, Maria Teresa
    Sieri, Sabina
    Tumino, Rosario
    Mattiello, Amalia
    Vagliano, Liliana
    Masala, Giovanna
    Ramon Quiros, J.
    Travier, Noemie
    Sanchez, Maria-Jose
    Larranaga, Nerea
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Chang-Claude, Jenny
    Kaaks, Rudolf
    Boeing, Heiner
    Clavel-Chapelon, Franc Oise
    Kvaskoff, Marina
    Dossus, Laure
    Trichopoulou, Antonia
    Benetou, Vassiliki
    Adarakis, George
    Bueno-de-Mesquita, H. B(As)
    Peeters, Petra H.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Andersson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Borgquist, Signe
    Butt, Salma
    Weiderpass, Elisabete
    Skeie, Guri
    Khaw, Kay-Tee
    Travis, Ruth C.
    Rinaldi, Sabina
    Romieu, Isabelle
    Gunter, Marc
    Kadi, Mai
    Riboli, Elio
    Vineis, Paolo
    Sacerdote, Carlotta
    Risk of second primary malignancies in women with breast cancer: Results from the European prospective investigation into cancer and nutrition (EPIC)2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 4, p. 940-948Article in journal (Refereed)
    Abstract [en]

    Women with a diagnosis of breast cancer are at increased risk of second primary cancers, and the identification of risk factors for the latter may have clinical implications. We have followed-up for 11 years 10,045 women with invasive breast cancer from a European cohort, and identified 492 second primary cancers, including 140 contralateral breast cancers. Expected and observed cases and Standardized Incidence Ratios (SIR) were estimated using Aalen-Johansen Markovian methods. Information on various risk factors was obtained from detailed questionnaires and anthropometric measurements. Cox proportional hazards regression models were used to estimate the role of risk factors. Women with breast cancer had a 30% excess risk for second malignancies (95% confidence interval-CI 18-42) after excluding contralateral breast cancers. Risk was particularly elevated for colorectal cancer (SIR, 1.71, 95% CI 1.43-2.00), lymphoma (SIR 1.80, 95% CI 1.31-2.40), melanoma (2.12; 1.63-2.70), endometrium (2.18; 1.75-2.70) and kidney cancers (2.40; 1.57-3.52). Risk of second malignancies was positively associated with age at first cancer, body mass index and smoking status, while it was inversely associated with education, post-menopausal status and a history of full-term pregnancy. We describe in a large cohort of women with breast cancer a 30% excess of second primaries. Among risk factors for breast cancer, a history of full-term pregnancy was inversely associated with the risk of second primary cancer. What's new? For the first time, researchers have used cohort data to show that people who survive breast cancer have a higher risk of developing another cancer later. By collecting data on 10,000 breast cancer patients over 11 years, these authors calculated a 30% boost in the patients' risk of developing a second primary malignancy, particularly colorectal cancer, lymphoma, melanoma, endometrial cancer, and kidney cancer. These findings, plus the data they collected on risk factors such as age, smoking, body mass index, and others, will help guide clinicians in screening procedures and follow up care for breast cancer patients.

  • 98. Rinaldi, S
    et al.
    Kaaks, R
    Friedenreich, CM
    Key, TJ
    Travis, R
    Biessy, C
    Slimani, N
    Overvad, K
    Ostergaard, JN
    Tjonneland, A
    Olsen, A
    Mesrine, S
    Fournier, A
    Dossus, L
    Lukanova, A
    Johnson, T
    Boeing, H
    Vigl, M
    Trichopoulou, A
    Benetou, V
    Trichopoulos, D
    Masala, G
    Krogh, V
    Tumino, R
    Ricceri, F
    Panico, S
    Bueno-de-Mesquita, HB
    Monninkhof, EM
    May, AM
    Weiderpass, E
    Quiros, JR
    Travier, N
    Molina-Montes, E
    Amiano, P
    Huerta, JM
    Ardanaz, E
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Johansson, M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, KT
    Wareham, N
    Scalbert, A
    Gunter, MJ
    Riboli, E
    Romieu, I
    Physical activity, sex steroid, and growth factor concentrations in pre- and post-menopausal women: a cross-sectional study within the EPIC cohort2014In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 25, no 1, p. 111-124Article in journal (Refereed)
    Abstract [en]

    Increased physical activity (PA) is associated with a reduced risk of several cancers. PA may reduce cancer risk by changing endogenous hormones levels, but relatively little research has focused on this topic. The purpose of this study was to elucidate the relation between PA and endogenous hormone concentrations. A cross-sectional analysis of 798 pre- and 1,360 post-menopausal women included as controls in case-control studies on endogenous hormones (steroids, progesterone, sex-hormone-binding globulin (SHBG), and growth factors) levels, and cancer risk nested within European Prospective Investigation into Cancer and Nutrition cohort was performed. Multivariate regression analyses were performed to compare geometric mean levels of hormones and SHBG by categories of PA. In pre-menopausal women, active women had 19 % significantly lower concentrations of androstenedione, 14 % lower testosterone, and 20 % lower free testosterone than inactive women, while no differences were observed for estrogens, progesterone, SHBG, and growth factors. In post-menopausal women, active women had 18 % significantly lower estradiol and 20 % lower free estradiol concentrations than inactive women, while no differences were observed for the other hormones and SHBG. More vigorous forms of physical activity were associated with higher insulin-like growth factor-I concentrations. Adjustment for body mass index did not alter the associations. Overall, the percentage of variance in hormone concentrations explained by PA levels was < 2 %. Our results support the hypothesis of an influence, although small in magnitude, of PA on sex hormone levels in blood, independent of body size.

  • 99. Ritte, Rebecca
    et al.
    Lukanova, Annekatrin
    Berrino, Franco
    Dossus, Laure
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Thure Filskov
    Overvad, Kim
    Clavel-Chapelon, Françoise
    Fournier, Agnès
    Fagherazzi, Guy
    Rohrmann, Sabine
    Teucher, Birgit
    Boeing, Heiner
    Aleksandrova, Krasimira
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Sieri, Sabina
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Quirós, José Ramón
    Buckland, Genevieve
    Sánchez, Maria-José
    Amiano, Pilar
    Chirlaque, María-Dolores
    Ardanaz, Eva
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bueno-de-Mesquita, Bas
    van Gils, Carla H
    Peeters, Petra Hm
    Krum-Hansen, Sanda
    Gram, Inger Torhild
    Lund, Eiliv
    Khaw, Kay-Tee
    Wareham, Nick
    Allen, Naomi E
    Key, Timothy J
    Romieu, Isabelle
    Rinaldi, Sabina
    Siddiq, Afshan
    Cox, David
    Riboli, Elio
    Kaaks, Rudolf
    Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study.2012In: Breast cancer research : BCR, ISSN 1465-542X, Vol. 14, no 3, p. R76-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: INTRODUCTION: Associations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use. METHODS: Within the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed. RESULTS: For risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m2 increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (Phet = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m2) than for more overweight women (BMI ≥25.9 kg/m2) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime. CONCLUSIONS: An elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women who never used HRT. Furthermore, postmenopausal HRT users were at an increased risk of ER-PR- as well as ER+PR+ tumors, especially among leaner women. For hormone-receptor positive tumors, but not for hormone-receptor negative tumors, our study confirms an inverse association of risk with BMI among young women of premenopausal age. Our data provide evidence for a possible role of sex hormones in the etiology of hormone-receptor negative tumors.

  • 100. Ritte, Rebecca
    et al.
    Lukanova, Annekatrin
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Mesrine, Sylvie
    Fagherazzi, Guy
    Dossus, Laure
    Teucher, Birgit
    Steindorf, Karen
    Boeing, Heiner
    Aleksandrova, Krasimira
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Grioni, Sara
    Mattiello, Amalia
    Tumino, Rosario
    Sacerdote, Carlotta
    Ramon Quiros, Jose
    Buckland, Genevieve
    Molina-Montes, Esther
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Amiano, Pilar
    Bueno-de-Mesquita, Bas
    van Duijnhoven, Franzel
    van Gils, Carla H.
    Peeters, Petra H. M.
    Wareham, Nick
    Khaw, Kay-Tee
    Key, Timothy J.
    Travis, Ruth C.
    Krum-Hansen, Sanda
    Gram, Inger Torhild
    Lund, Eiliv
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Andersson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Romieu, Isabelle
    Rinaldi, Sabina
    McCormack, Valerie
    Riboli, Elio
    Kaaks, Rudolf
    Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer: A cohort study2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 132, no 11, p. 2619-2629Article in journal (Refereed)
    Abstract [en]

    Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European Prospective Investigation into Cancer and Nutrition cohort, Cox proportional hazards models were used to describe the relationships of adult height, leg length and sitting height and age at menarche with risk of estrogen and progesterone receptor negative (ER-PR-) (n = 990) and ER+PR+ (n = 3,524) breast tumors. Height as a single risk factor was compared to a model combining leg length and sitting height. The possible interactions of height, leg length and sitting height with menarche were also analyzed. Risk of both ER-PR- and ER+PR+ malignancies was positively associated with standing height, leg length and sitting height and inversely associated with increasing age at menarche. For ER+PR+ disease, sitting height (hazard ratios: 1.14[95% confidence interval: 1.081.20]) had a stronger risk association than leg length (1.05[1.001.11]). In comparison, for ER-PR- disease, no distinct differences were observed between leg length and sitting height. Women who were tall and had an early menarche (13 years) showed an almost twofold increase in risk of ER+PR+ tumors but no such increase in risk was observed for ER-PR- disease. Indicators of exposures during rapid growth periods were associated with risks of both HR-defined breast cancers. Exposures during childhood promoting faster development may establish risk associations for both HR-positive and negative malignancies. The stronger associations of the components of height with ER+PR+ tumors among older women suggest possible hormonal links that could be specific for postmenopausal women.

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