title: A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer.
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.
authors.affiliation: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA.
authors.forename: Alice W
authors.initials: AW
authors.lastname: Lee
authors.affiliation: Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI.
authors.forename: Ashley
authors.initials: A
authors.lastname: Bomkamp
authors.affiliation: Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
authors.forename: Elisa V
authors.initials: EV
authors.lastname: Bandera
authors.affiliation: Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Jensen
authors.affiliation: University of New South Wales, Sydney, Australia.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.affiliation: Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.|Department of Biomedical Sciences, Community and Population Health Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Marc T
authors.initials: MT
authors.lastname: Goodman
authors.affiliation: Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.|Department of Epidemiology, University of Washington, Seattle, WA.
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Rossing
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA.|Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA.
authors.forename: Francesmary
authors.initials: F
authors.lastname: Modugno
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY.
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Moysich
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Rudolph
authors.affiliation: Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Gentry-Maharaj
authors.affiliation: Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.|Harvard T.H. Chan School of Public Health, Boston, MA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Terry
authors.affiliation: Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.|Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
authors.affiliation: Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.|Harvard T.H. Chan School of Public Health, Boston, MA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Cramer
authors.affiliation: Department of Epidemiology, The Geisel School of Medicine at Dartmouth, Hanover, NH.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doherty
authors.affiliation: Department of Public Health Sciences, The University of Virginia, Charlottesville, VA.
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
authors.affiliation: Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.|Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Kjaer
authors.affiliation: University of Texas School of Public Health, Houston, TX.
authors.forename: Roberta B
authors.initials: RB
authors.lastname: Ness
authors.affiliation: Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Usha
authors.initials: U
authors.lastname: Menon
authors.affiliation: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC.
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.affiliation: Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI.|Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI.
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
authors.affiliation: Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, Los Angeles, CA.
authors.forename: Lynda
authors.initials: L
authors.lastname: Roman
authors.affiliation: Department of Public Health and Primary Care, Center for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom.|Department of Oncology, Center for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Sara
authors.initials: S
authors.lastname: Olson
authors.affiliation: Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.|Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Estrid
authors.initials: E
authors.lastname: Hogdall
authors.affiliation: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.affiliation: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Pike
authors.affiliation: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.affiliation: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA. lpearce@umich.edu.|Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI. lpearce@umich.edu.
authors.forename: Celeste Leigh
authors.initials: CL
authors.lastname: Pearce
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D017398:Alternative Splicing; D016022:Case-Control Studies; D004198:Disease Susceptibility; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000453:epidemiology* / Q000209:etiology*; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D012306:Risk; D019098:Telomerase / Q000235:genetics*
chemical_list: C509186:TERT protein, human; D019098:Telomerase
keywords: SNPs; estrogen; gene-environment interactions; hormone therapy; ovarian cancer