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Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

Authors :
Madalene Earp
Jonathan P Tyrer
Stacey J Winham
Hui-Yi Lin
Ganna Chornokur
Joe Dennis
Katja K H Aben
Hoda Anton-Culver
Natalia Antonenkova
Elisa V Bandera
Yukie T Bean
Matthias W Beckmann
Line Bjorge
Natalia Bogdanova
Louise A Brinton
Angela Brooks-Wilson
Fiona Bruinsma
Clareann H Bunker
Ralf Butzow
Ian G Campbell
Karen Carty
Jenny Chang-Claude
Linda S Cook
Daniel W Cramer
Julie M Cunningham
Cezary Cybulski
Agnieszka Dansonka-Mieszkowska
Evelyn Despierre
Jennifer A Doherty
Thilo Dörk
Andreas du Bois
Matthias Dürst
Douglas F Easton
Diana M Eccles
Robert P Edwards
Arif B Ekici
Peter A Fasching
Brooke L Fridley
Aleksandra Gentry-Maharaj
Graham G Giles
Rosalind Glasspool
Marc T Goodman
Jacek Gronwald
Philipp Harter
Alexander Hein
Florian Heitz
Michelle A T Hildebrandt
Peter Hillemanns
Claus K Hogdall
Estrid Høgdall
Satoyo Hosono
Edwin S Iversen
Anna Jakubowska
Allan Jensen
Bu-Tian Ji
Audrey Y Jung
Beth Y Karlan
Melissa Kellar
Lambertus A Kiemeney
Boon Kiong Lim
Susanne K Kjaer
Camilla Krakstad
Jolanta Kupryjanczyk
Diether Lambrechts
Sandrina Lambrechts
Nhu D Le
Shashi Lele
Jenny Lester
Douglas A Levine
Zheng Li
Dong Liang
Jolanta Lissowska
Karen Lu
Jan Lubinski
Lene Lundvall
Leon F A G Massuger
Keitaro Matsuo
Valerie McGuire
John R McLaughlin
Iain McNeish
Usha Menon
Roger L Milne
Francesmary Modugno
Kirsten B Moysich
Roberta B Ness
Heli Nevanlinna
Kunle Odunsi
Sara H Olson
Irene Orlow
Sandra Orsulic
James Paul
Tanja Pejovic
Liisa M Pelttari
Jenny B Permuth
Malcolm C Pike
Elizabeth M Poole
Barry Rosen
Mary Anne Rossing
Joseph H Rothstein
Ingo B Runnebaum
Iwona K Rzepecka
Eva Schernhammer
Ira Schwaab
Xiao-Ou Shu
Yurii B Shvetsov
Nadeem Siddiqui
Weiva Sieh
Honglin Song
Melissa C Southey
Beata Spiewankiewicz
Lara Sucheston-Campbell
Ingvild L Tangen
Soo-Hwang Teo
Kathryn L Terry
Pamela J Thompson
Lotte Thomsen
Shelley S Tworoger
Anne M van Altena
Ignace Vergote
Liv Cecilie Vestrheim Thomsen
Robert A Vierkant
Christine S Walsh
Shan Wang-Gohrke
Nicolas Wentzensen
Alice S Whittemore
Kristine G Wicklund
Lynne R Wilkens
Yin-Ling Woo
Anna H Wu
Xifeng Wu
Yong-Bing Xiang
Hannah Yang
Wei Zheng
Argyrios Ziogas
Alice W Lee
Celeste L Pearce
Andrew Berchuck
Joellen M Schildkraut
Susan J Ramus
Alvaro N A Monteiro
Steven A Narod
Thomas A Sellers
Simon A Gayther
Linda E Kelemen
Georgia Chenevix-Trench
Harvey A Risch
Paul D P Pharoah
Ellen L Goode
Catherine M Phelan
Source :
PLoS ONE, Vol 13, Iss 7, p e0197561 (2018)
Publication Year :
2018
Publisher :
Public Library of Science (PLoS), 2018.

Abstract

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
19326203
Volume :
13
Issue :
7
Database :
Directory of Open Access Journals
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
edsdoj.0902fb510b894b23853bcbfa1b7a29ec
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pone.0197561