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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.

SUBMITTER: Lee AW

PROVIDER: S-EPMC5500237 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Lee Alice W AW Bomkamp Ashley A Bandera Elisa V EV Jensen Allan A Ramus Susan J SJ Goodman Marc T MT Rossing Mary Anne MA Modugno Francesmary F Moysich Kirsten B KB Chang-Claude Jenny J Rudolph Anja A Gentry-Maharaj Aleksandra A Terry Kathryn L KL Gayther Simon A SA Cramer Daniel W DW Doherty Jennifer A JA Schildkraut Joellen M JM Kjaer Susanne K SK Ness Roberta B RB Menon Usha U Berchuck Andrew A Mukherjee Bhramar B Roman Lynda L Pharoah Paul D PD Chenevix-Trench Georgia G Olson Sara S Hogdall Estrid E Wu Anna H AH Pike Malcolm C MC Stram Daniel O DO Pearce Celeste Leigh CL

International journal of cancer 20160916 12

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 partici ...[more]

PMID: 27420401

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Project description:OBJECTIVE:To describe the association between postmenopausal estrogen-only therapy use and risk of ovarian carcinoma, specifically with regard to disease histotype and duration and timing of use. METHODS:We conducted a pooled analysis of 906 women with ovarian carcinoma and 1,220 women in a control group; all 2,126 women included reported having had a hysterectomy. Ten population-based case-control studies participating in the Ovarian Cancer Association Consortium, an international consortium whose goal is to combine data from many studies with similar methods so reliable assessments of risk factors can be determined, were included. Self-reported questionnaire data from each study were harmonized and conditional logistic regression was used to examine estrogen-only therapy's histotype-specific and duration and recency of use associations. RESULTS:Forty-three and a half percent of the women in the control group reported previous use of estrogen-only therapy. Compared with them, current or recent estrogen-only therapy use was associated with an increased risk for the serous (51.4%, odds ratio [OR] 1.63, 95% confidence interval [CI] 1.27-2.09) and endometrioid (48.6%, OR 2.00, 95% CI 1.17-3.41) histotypes. In addition, statistically significant trends in risk according to duration of use were seen among current or recent postmenopausal estrogen-only therapy users for both ovarian carcinoma histotypes (Ptrend<.001 for serous and endometrioid). Compared with women in the control group, current or recent users for 10 years or more had increased risks of serous ovarian carcinoma (36.8%, OR 1.73, 95% CI 1.26-2.38) and endometrioid ovarian carcinoma (34.9%, OR 4.03, 95% CI 1.91-8.49). CONCLUSION:We found evidence of an increased risk of serous and endometrioid ovarian carcinoma associated with postmenopausal estrogen-only therapy use, particularly of long duration. These findings emphasize that risk may be associated with extended estrogen-only therapy use.

Project description:Alternative splicing of precursor mRNA is a fundamental mechanism to generate multiple proteins from a single gene. Although constitutive and alternative mRNA splicing is temporally and spatially regulated, deregulation of mRNA splicing could cause development, progression, and metastasis of tumors. Through yeast two-hybrid screening of a human breast cDNA library using estrogen receptor-alpha (ERalpha) as bait, we identified a novel nuclear receptor box containing full-length protein, nuclear protein E3-3 (NPE3-3). Our results revealed that NPE3-3 associates with not only ERalpha but also with splicing factors, serine/arginine-rich protein (SRp)-30c, SRp40, and splicing factor SC-35, suggesting that NPE3-3 is likely to be involved in regulation of mRNA splicing. Accordingly, transient expression of NPE3-3 in cells resulted in expected splicing of the CD44 control minigene. We also discovered that NPE3-3-overexpressing clones produced a novel, previously unrecognized, alternatively spliced variant of ERalpha (termed ERalphaV), which had a molecular size of 37 kDa composed of only exons 1, 2, 7, and 8. ERalphaV was expressed and sequestered in the cytoplasm in MCF-7 cells stably overexpressing NPE3-3, suggesting its involvement in nongenomic hormone signaling. NPE3-3 clones exhibited up-regulation of ERK1/2 signaling, cyclin D1, and cathepsin D and enhanced tumor cell proliferation, migration, and tumorigenicity. Moreover, direct expression of the ERalphaV in breast cancer cells stimulated ERK1/2 up-regulation and cyclin D1 expression. We found that ERalphaV physically interacted with MAPK kinase (MEK)-1/2, and thus, an ERalphaV and MEK1/2 complex could lead to the activation of the ERK1/2 pathway. Interestingly, NPE3-3 was up-regulated in human breast tumors. These findings revealed a role for NPE3-3 in alternative splicing and suggest that ERalpha is a physiological target of NPE3-3, leading to a constitutive nongenomic signaling pathway in breast cancer cells.

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

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

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