TY - JOUR

T1 - rs495139 in the TYMS-ENOSF1 region and risk of ovarian carcinoma of mucinous histology

AU - Kelemen, Linda E.

AU - Earp, Madalene

AU - Fridley, Brooke L.

AU - Chenevix-Trench, Georgia

AU - Fasching, Peter A.

AU - Beckmann, Matthias W.

AU - Ekici, Arif B.

AU - Hein, Alexander

AU - Lambrechts, Diether

AU - Lambrechts, Sandrina

AU - Van Nieuwenhuysen, Els

AU - Vergote, Ignace

AU - Rossing, Mary Anne

AU - Doherty, Jennifer A.

AU - Chang-Claude, Jenny

AU - Behrens, Sabine

AU - Moysich, Kirsten B.

AU - Cannioto, Rikki

AU - Lele, Shashikant

AU - Odunsi, Kunle

AU - Goodman, Marc T.

AU - Shvetsov, Yurii B.

AU - Thompson, Pamela J.

AU - Wilkens, Lynne R.

AU - Dörk, Thilo

AU - Antonenkova, Natalia

AU - Bogdanova, Natalia

AU - Hillemanns, Peter

AU - Runnebaum, Ingo B.

AU - Bois, Andreas Du

AU - Harter, Philipp

AU - Heitz, Florian

AU - Schwaab, Ira

AU - Butzow, Ralf

AU - Pelttari, Liisa M.

AU - Nevanlinna, Heli

AU - Modugno, Francesmary

AU - Edwards, Robert P.

AU - Kelley, Joseph L.

AU - Ness, Roberta B.

AU - Karlan, Beth Y.

AU - Lester, Jenny

AU - Orsulic, Sandra

AU - Walsh, Christine

AU - Kjaer, Susanne K.

AU - Hogdall, Estrid

AU - Engelholm, Svend Aage

AU - Hogdall, Claus

AU - Lundvall, Lene

AU - Nedergaard, Lotte

AU - Australian Ovarian Cancer Study Group

AU - Ovarian Cancer Association Consortium

PY - 2018

Y1 - 2018

N2 - Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97-1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03-1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10 −28 ), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

AB - Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97-1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03-1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10 −28 ), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

KW - Consortia

KW - Enolase superfamily member 1

KW - Expression quantitative trait locus

KW - Genetics

KW - Gynecology

KW - Ovarian neoplasms

KW - Single-nucleotide polymorphism

KW - Thymidylate synthase

U2 - 10.3390/ijms19092473

DO - 10.3390/ijms19092473

M3 - Journal article

C2 - 30134598

AN - SCOPUS:85052837195

VL - 19

JO - International Journal of Molecular Sciences (CD-ROM)

JF - International Journal of Molecular Sciences (CD-ROM)

SN - 1424-6783

IS - 9

M1 - 2473

ER -