Abstract 797: A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer
Authors: Lee Alice W. , Bomkamp Ashley , Bandera Elisa V. , Jensen Allan , Ramus Susan J. , Goodman Marc T. , Rossing Mary Anne , Modugno Francesmary , Moysich Kirsten B. , Chang-Claude Jenny , Rudolph Anja , Gentry-Maharaj Aleksandra , Terry Kathryn L. , Gayther Simon A. , Cramer Daniel W. , Doherty Jennfier A. , Schildkraut Joellen M. , Kjaer Susanne K. , Ness Roberta B. , Menon Usha , Berchuck Andrew , Mukherjee Bhramar , Roman Lynda , Pharoah Paul D. , Chenevix-Trench Georgia , Wu Anna H. , Pike Malcolm C. , Pearce Celeste L. 
Published: July 2016

Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian carcinoma. Genetics also plays an important role in ovarian carcinoma etiology, which is partly attributable to 18 confirmed susceptibility loci identified by genome-wide association studies (GWASs). Each of these common variants is associated with a modest relative risk estimate, but it is possible that interactions between non-genetic and genetic risk factors exist, thereby putting some women at higher risk. This interplay among the 18 loci, ET use, and ovarian carcinoma risk has yet to be evaluated.

In our analysis, we used individual questionnaire 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). The genotype data was based on information from three GWASs, their replication efforts, and two large-scale arrays. Conditional logistic regression was used to determine the association between the 18 confirmed variants and risk of serous and endometrioid ovarian carcinoma among ET users and non-users separately. A likelihood ratio test was used to test for statistical interaction (i.e., departure from a multiplicative model).

After controlling for well-established ovarian carcinoma risk factors as well as genetic ancestry, a splicing variant in TERT, rs10069690, showed a significant interaction with ET use for risk of serous ovarian carcinoma (pint = 0.014). ET users carrying the T allele had a 50% increased risk of disease (OR = 1.50, 95% CI 1.16-1.93); the impact of this allele was even stronger for long-term ET users of 10+ years (OR = 2.13, 95% CI 1.39-2.37, pint = 0.036). Non-ET users showed essentially no association with the disease (OR = 1.09, 95% CI 0.97-1.22). In addition, two SNPS, rs7207826 (C allele) and rs56318008 (T allele), in other genomic regions had significant interactions with ET use for the endometrioid histotype (pint = 0.030 and pint = 0.042, respectively).

Overall, we have shown evidence of statistical interactions between postmenopausal ET use and three confirmed ovarian cancer susceptibility alleles with risk of serous and endometrioid ovarian cancer. We observed four statistically significant interactions, which is twice as many as would be expected by chance at the p≤0.05 level, although none survived correction for multiple comparisons. This is the first study, to our knowledge, to suggest potential gene-environment interactions in ovarian carcinoma in the context of hormone therapy use with confirmed susceptibility alleles. It is also intriguing that the identified interactions include confirmed variants that are located in or adjacent to genes in which estrogen is biologically involved. These findings, if replicated, may be critical for future risk prediction modeling.

Citation Format: 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, Jennfier 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, Anna H. Wu, Malcolm C. Pike, Celeste L. Pearce. A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 797.