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

rs495139 in the TYMS-ENOSF1 region and risk of ovarian carcinoma of mucinous histology
rs495139 in the TYMS-ENOSF1 region and risk of ovarian carcinoma of mucinous histology
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.
1422-0067
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Carty, Karen
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Glasspool, Rosalind
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Campbell, Ian
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Eccles, Diana
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Whittemore, Alice
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Mcguire, Valerie
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Rothstein, Joseph
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Sieh, Weiva
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Phelan, Catherine
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Mclaughlin, John
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Risch, Harvey
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Anton-culver, Hoda
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Ziogas, Argyrios
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Menon, Usha
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Gayther, Simon
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Gentry-maharaj, Aleksandra
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Pearce, Celeste
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Kupryjanczyk, Jolanta
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Podgorska, Agnieszka
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Plisiecka-halasa, Joanna
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Sawicki, Wlodzimierz
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Goode, Ellen
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Kelemen, Linda, Earp, Madalene, Fridley, Brooke, Chenevix-trench, Georgia, 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 and Berchuck, Andrew (2018) rs495139 in the TYMS-ENOSF1 region and risk of ovarian carcinoma of mucinous histology. International Journal of Molecular Sciences, 19 (9), [2473]. (doi:10.3390/ijms19092473).

Record type: Article

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.

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Accepted/In Press date: 9 August 2018
e-pub ahead of print date: 21 August 2018
Published date: 21 August 2018

Identifiers

Local EPrints ID: 424557
URI: http://eprints.soton.ac.uk/id/eprint/424557
ISSN: 1422-0067
PURE UUID: 6c007993-024b-4ac8-bc0f-87621d50484d
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 05 Oct 2018 11:38
Last modified: 22 Nov 2021 02:35

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Contributors

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

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