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

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

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Abstract

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.

Original languageEnglish
Article number2473
Number of pages13
JournalInternational Journal of Molecular Sciences
Volume19
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

Keywords

  • Consortia
  • Enolase superfamily member 1
  • Expression quantitative trait locus
  • Genetics
  • Gynecology
  • Ovarian neoplasms
  • Single-nucleotide polymorphism
  • Thymidylate synthase

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