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Int J Cancer. 2016 Dec 15;139(12):2646-2654. doi: 10.1002/ijc.30274. Epub 2016 Sep 16.

A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer.

Author information

1
Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA.
2
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI.
3
Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
4
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
5
University of New South Wales, Sydney, Australia.
6
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
7
Department of Biomedical Sciences, Community and Population Health Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
8
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
9
Department of Epidemiology, University of Washington, Seattle, WA.
10
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA.
11
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA.
12
Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA.
13
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY.
14
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
15
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
16
Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.
17
Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
18
Harvard T.H. Chan School of Public Health, Boston, MA.
19
Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
20
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA.
21
Department of Epidemiology, The Geisel School of Medicine at Dartmouth, Hanover, NH.
22
Department of Public Health Sciences, The University of Virginia, Charlottesville, VA.
23
Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
24
University of Texas School of Public Health, Houston, TX.
25
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC.
26
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI.
27
Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, Los Angeles, CA.
28
Department of Public Health and Primary Care, Center for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom.
29
Department of Oncology, Center for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
30
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
31
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
32
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
33
Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA. lpearce@umich.edu.
34
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI. lpearce@umich.edu.

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.

KEYWORDS:

SNPs; estrogen; gene-environment interactions; hormone therapy; ovarian cancer

PMID:
27420401
PMCID:
PMC5500237
DOI:
10.1002/ijc.30274
[Indexed for MEDLINE]
Free PMC Article

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