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  • Author: Jolanta Lissowska x
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Anja Rudolph, Rebecca Hein, Sara Lindström, Lars Beckmann, Sabine Behrens, Jianjun Liu, Hugues Aschard, Manjeet K Bolla, Jean Wang, Thérèse Truong, Emilie Cordina-Duverger, Florence Menegaux, Thomas Brüning, Volker Harth, The GENICA Network, Gianluca Severi, Laura Baglietto, Melissa Southey, Stephen J Chanock, Jolanta Lissowska, Jonine D Figueroa, Mikael Eriksson, Keith Humpreys, Hatef Darabi, Janet E Olson, Kristen N Stevens, Celine M Vachon, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Penny M Webb, kConFab Investigators, AOCS Management Group, Pascal Guénel, Hiltrud Brauch, Graham Giles, Montserrat García-Closas, Kamila Czene, Georgia Chenevix-Trench, Fergus J Couch, Irene L Andrulis, Anthony Swerdlow, David J Hunter, Dieter Flesch-Janys, Douglas F Easton, Per Hall, Heli Nevanlinna, Peter Kraft, Jenny Chang-Claude and on behalf of the Breast Cancer Association Consortium

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case–control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (P int) <3.0×10−3 were selected for replication using pooled case–control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined P int. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined P int≤8.9×10−6), two SNPs in SLC25A21 (combined P int≤4.8×10−5), and three SNPs in PLCG2 (combined P int≤4.5×10−5). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined P int≤2.7×10−5), one SNP in CD80 (combined P int≤8.2×10−6), three SNPs on chr17 near TMEM132E (combined P int≤2.2×10−6), and two SNPs on chr18 near SLC25A52 (combined P int≤4.6×10−5). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.

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Catherine M Olsen, Christina M Nagle, David C Whiteman, Roberta Ness, Celeste Leigh Pearce, Malcolm C Pike, Mary Anne Rossing, Kathryn L Terry, Anna H Wu, The Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group, Harvey A Risch, Herbert Yu, Jennifer A Doherty, Jenny Chang-Claude, Rebecca Hein, Stefan Nickels, Shan Wang-Gohrke, Marc T Goodman, Michael E Carney, Rayna K Matsuno, Galina Lurie, Kirsten Moysich, Susanne K Kjaer, Allan Jensen, Estrid Hogdall, Ellen L Goode, Brooke L Fridley, Robert A Vierkant, Melissa C Larson, Joellen Schildkraut, Cathrine Hoyo, Patricia Moorman, Rachel P Weber, Daniel W Cramer, Allison F Vitonis, Elisa V Bandera, Sara H Olson, Lorna Rodriguez-Rodriguez, Melony King, Louise A Brinton, Hannah Yang, Montserrat Garcia-Closas, Jolanta Lissowska, Hoda Anton-Culver, Argyrios Ziogas, Simon A Gayther, Susan J Ramus, Usha Menon, Aleksandra Gentry-Maharaj and Penelope M Webb

Whilst previous studies have reported that higher BMI increases a woman's risk of developing ovarian cancer, associations for the different histological subtypes have not been well defined. As the prevalence of obesity has increased dramatically, and classification of ovarian histology has improved in the last decade, we sought to examine the association in a pooled analysis of recent studies participating in the Ovarian Cancer Association Consortium. We evaluated the association between BMI (recent, maximum and in young adulthood) and ovarian cancer risk using original data from 15 case–control studies (13 548 cases and 17 913 controls). We combined study-specific adjusted odds ratios (ORs) using a random-effects model. We further examined the associations by histological subtype, menopausal status and post-menopausal hormone use. High BMI (all time-points) was associated with increased risk. This was most pronounced for borderline serous (recent BMI: pooled OR=1.24 per 5 kg/m2; 95% CI 1.18–1.30), invasive endometrioid (1.17; 1.11–1.23) and invasive mucinous (1.19; 1.06–1.32) tumours. There was no association with serous invasive cancer overall (0.98; 0.94–1.02), but increased risks for low-grade serous invasive tumours (1.13, 1.03–1.25) and in pre-menopausal women (1.11; 1.04–1.18). Among post-menopausal women, the associations did not differ between hormone replacement therapy users and non-users. Whilst obesity appears to increase risk of the less common histological subtypes of ovarian cancer, it does not increase risk of high-grade invasive serous cancers, and reducing BMI is therefore unlikely to prevent the majority of ovarian cancer deaths. Other modifiable factors must be identified to control this disease.