A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer
Year: 2016
Type: article
Study design: Observational Study
Abstract: Menopausal estrogen‐alone therapy (ET) is a well‐established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome‐wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case–control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non‐users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (pint = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19–1.91), which was stronger for long‐term ET users of 10+ years (OR = 1.85, 95% CI 1.28–2.66, pint = 0.034). Non‐users showed essentially no association (OR = 1.08, 95% CI 0.96–1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (pint = 0.021 and pint = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow‐up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.
Source: International Journal of Cancer
DOI: 10.1002/ijc.30274
Authors: Alice W. Lee, Ashley Bomkamp, Elisa V. Bandera, Allan Jensen, Susan J. Ramus, Marc T. Goodman, Mary Anne Rossing, Francesmary Modugno, Kirsten B. Moysich, Jenny Chang‐Claude, Anja Rudolph, Aleksandra Gentry‐Maharaj, Kathryn L. Terry, Simon A. Gayther, Daniel W. Cramer, Jennifer A. Doherty, Joellen M. Schildkraut, Susanne K. Kjaer, Roberta B. Ness, Usha Menon, Andrew Berchuck, Bhramar Mukherjee, Lynda Roman, Paul D. Pharoah, Georgia Chenevix‐Trench, Sara Olson, Estrid Hogdall, Anna H. Wu, Malcolm C. Pike, Daniel O. Stram, Celeste Leigh Pearce
Institutions: University of Southern California, University of Michigan, Rutgers Cancer Institute, Danish Cancer Society, UNSW Sydney, Cedars-Sinai Medical Center, University of Washington, Fred Hutch Cancer Center, University of Pittsburgh, Magee-Womens Research Institute, UPMC Hillman Cancer Center, Roswell Park Comprehensive Cancer Center, German Cancer Research Center, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, University College London, Brigham and Women's Hospital, Harvard University, Dartmouth College, Dartmouth Health, University of Virginia, University of Copenhagen, Rigshospitalet, Duke Medical Center, University of Cambridge, QIMR Berghofer Medical Research Institute, Memorial Sloan Kettering Cancer Center, Herlev Hospital
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: Ovarian Cancer Research Fund, Roswell Park Cancer Institute, Memorial Sloan-Kettering Cancer Center, Rutgers Cancer Institute of New Jersey, Francis Crick Institute, Cancer Research UK, National Institute for Health and Care Research, University College London, European Commission, Bundesministerium für Bildung und Forschung, Universiteit Stellenbosch, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, Seventh Framework Programme, National Institute on Aging, National Cancer Institute, National Institute of Environmental Health Sciences, National Center for Research Resources, Medical Research and Materiel Command
Awards: SURVEILLANCE EPIDEMIOLOGY &END RESULTS PROGRAM, G1044543555, G1132776228, G1174786237, G1284677684, G1339933430, G1404790370, G1409071184, G1414722911, G1478067267, G1480891745, RISK FACTORS AND PROGNOSTIC FACTORS FOR OVARIAN CANCER, G1757939464, G1885355073, G1895826331, SURVEILLANCE EPIDEMIOLOGY AND END RESULTS, G204658482, G2051006376, G2066431456, G213336435, Ovarian Cancer and Gonadotropin Signaling, G2203820619, G2307404120, G2373099447, G2437083349, G2449870768, G2519210884, G2689393783, G2730293317, Obesity in ovarian cancer prognosis, G2838565599, G289723095, G2899816875, G3120360579, G3221852482, G3307645897, General Clinical Research Center, G3670273158, ESTROGEN, DIET, GENETICS AND ENDOMETRIAL CANCER, G3921292984, G4102770861, G410854802, G4119975330, G4162991602, G4873239205, Collaborative Genetic Study of Ovarian Cancer Risk, CASE-CONTROL STUDY OF OVARIAN CANCER IN LOS ANGELES, G566671978, G5850682332, G6283257732, G6466116822, G6651302240, Inflammation and Ovarian Cancer, G6978709651, G7378152860, G7756110719, G7903046090, G835684289, Collaborative Oncological Gene-environment Study, Novel immunological biomarkers ovarian cancer prognosis, G8970693615, G9000001642, G9000003249, G9000004104, G9000005129, G9000016153, G9000031556, G9000031659, G9000038231, G9000039166, G9000039344, G9000056976, G9000058088, G9000076967, G9000077506, G9000143528, G9000148858, G9000155148, G9000164272, G9000207620, G9000243861, G9000273410, Cancer Center Support Grant, Cancer Center Support Grant, University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG)
OpenAlex ID: W2497370875