rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology
Authors: Kelemen Linda , Earp Madalene , Fridley Brooke , Chenevix-Trench Georgia ,   On behalf of Australian Ovarian Cancer Study Group, Fasching Peter , Beckmann Matthias , Ekici Arif , Hein Alexander , Lambrechts Diether , Lambrechts Sandrina , Van Nieuwenhuysen Els , Vergote Ignace , Rossing Mary , Doherty Jennifer , Chang-Claude Jenny , Behrens Sabine , Moysich Kirsten , Cannioto Rikki , Lele Shashikant , Odunsi Kunle , Goodman Marc , Shvetsov Yurii , Thompson Pamela , Wilkens Lynne , Dörk Thilo , Antonenkova Natalia , Bogdanova Natalia , Hillemanns Peter , Runnebaum Ingo , Du Bois Andreas , Harter Philipp , Heitz Florian , Schwaab Ira , Butzow Ralf , Pelttari Liisa , Nevanlinna Heli , Modugno Francesmary , Edwards Robert , Kelley Joseph , Ness Roberta , Karlan Beth , Lester Jenny , Orsulic Sandra , Walsh Christine , Kjaer Susanne , Jensen Allan , Cunningham Julie , Vierkant Robert , Giles Graham , Bruinsma Fiona , Southey Melissa , Hildebrandt Michelle , Liang Dong , Lu Karen , Wu Xifeng , Sellers Thomas , Levine Douglas , Schildkraut Joellen , Iversen Edwin , Terry Kathryn , Cramer Daniel , Tworoger Shelley , Poole Elizabeth , Bandera Elisa , Olson Sara , Orlow Irene , Vestrheim Thomsen Liv , Bjorge Line , Krakstad Camilla , Tangen Ingvild , Kiemeney Lambertus , Aben Katja , Massuger Leon , Van Altena Anne , Pejovic Tanja , Bean Yukie , Kellar Melissa , Cook Linda , Le Nhu , Brooks-Wilson Angela , Gronwald Jacek , Cybulski Cezary , Jakubowska Anna , Lubiński Jan , Wentzensen Nicolas , Brinton Louise , Lissowska Jolanta , Hogdall Estrid , Engelholm Svend , Hogdall Claus , Lundvall Lene , Nedergaard Lotte , Pharoah Paul , Dicks Ed , Song Honglin , Tyrer Jonathan , McNeish Iain , Siddiqui Nadeem , Carty Karen , Glasspool Rosalind , Paul James , Campbell Ian , Eccles Diana , Whittemore Alice , McGuire Valerie , Rothstein Joseph , Sieh Weiva , Narod Steven , Phelan Catherine , McLaughlin John , Risch Harvey , Anton-Culver Hoda , Ziogas Argyrios , Menon Usha , Gayther Simon , Gentry-Maharaj Aleksandra , Ramus Susan , Wu Anna , Pearce Celeste , Lee Alice , Pike Malcolm , Kupryjanczyk Jolanta , Podgorska Agnieszka , Plisiecka-Halasa Joanna , Sawicki Wlodzimierz , Goode Ellen , Berchuck Andrew ,   Ovarian Cancer Association Consortium
Published: August 2018

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.