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

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility
Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility
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.
1932-6203
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Earp, Madalene, Tyrer, Jonathan P., Winham, Stacey J., Lin, Hui-yi, Chornokur, Ganna, Dennis, Joe, Aben, Katja K. H., Anton‐culver, Hoda, Antonenkova, Natalia, Bandera, Elisa V., Bean, Yukie T., Beckmann, Matthias W., Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A., Brooks-wilson, Angela, Bruinsma, Fiona, Bunker, Clareann H., Butzow, Ralf, Campbell, Ian G., Carty, Karen, Chang-claude, Jenny, Cook, Linda S., Cramer, Daniel W, Cunningham, Julie M., Cybulski, Cezary, Dansonka-mieszkowska, Agnieszka, Despierre, Evelyn, Doherty, Jennifer A., Dörk, Thilo, Du Bois, Andreas, Dürst, Matthias, Easton, Douglas F., Eccles, Diana M., Edwards, Robert P., Ekici, Arif B., Fasching, Peter A., Fridley, Brooke L., Gentry-maharaj, Aleksandra, Giles, Graham G., Glasspool, Rosalind, Goodman, Marc T., Gronwald, Jacek, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle A. T., Hillemanns, Peter, Hogdall, Claus K., Høgdall, Estrid, Hosono, Satoyo, Iversen, Edwin S., Jakubowska, Anna, Jensen, Allan, Ji, Bu-tian, Jung, Audrey Y., Karlan, Beth Y., Kellar, Melissa, Kiemeney, Lambertus A., Kiong Lim, Boon, Kjaer, Susanne K., Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D., Lele, Shashi, Lester, Jenny, Levine, Douglas A., Li, Zheng, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon F. A. G., Matsuo, Keitaro, Mcguire, Valerie, Mclaughlin, John R., Mcneish, Iain, Menon, Usha, Milne, Roger L., Modugno, Francesmary, Moysich, Kirsten B., Ness, Roberta B., Nevanlinna, Heli, Odunsi, Kunle, Olson, Sara H., Orlow, Irene, Orsulic, Sandra, Paul, James, Pejovic, Tanja, Pelttari, Liisa M., Permuth, Jenny B., Pike, Malcolm C., Poole, Elizabeth M., Rosen, Barry, Rossing, Mary Anne, Rothstein, Joseph H., Runnebaum, Ingo B., Rzepecka, Iwona K., Schernhammer, Eva, Schwaab, Ira, Shu, Xiao-ou, Shvetsov, Yurii B., Siddiqui, Nadeem, Sieh, Weiva, Song, Honglin, Southey, Melissa C., Spiewankiewicz, Beata, Sucheston-campbell, Lara, Tangen, Ingvild L., Teo, Soo-hwang, Terry, Kathryn L., Thompson, Pamela J., Thomsen, Lotte, Tworoger, Shelley S., Van Altena, Anne M., Vergote, Ignace, Vestrheim Thomsen, Liv Cecilie, Vierkant, Robert A., Walsh, Christine S., Wang-gohrke, Shan, Wentzensen, Nicolas, Whittemore, Alice S., Wicklund, Kristine G., Wilkens, Lynne R., Woo, Yin-ling, Wu, Anna H., Wu, Xifeng, Xiang, Yong-bing, Yang, Hannah, Zheng, Wei, Ziogas, Argyrios, Lee, Alice W, Pearce, Celeste L., Berchuck, Andrew, Schildkraut, Joellen M., Ramus, Susan J., Monteiro, Alvaro N. A., Narod, Steven A., Sellers, Thomas A., Gayther, Simon A., Kelemen, Linda E., Chenevix-trench, Georgia, Risch, Harvey A., Pharoah, Paul D. P., Goode, Ellen L. and Phelan, Catherine M. , Scott, Rodney John (ed.) (2018) Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility. PLoS ONE, 13 (7), e0197561. (doi:10.1371/journal.pone.0197561).

Record type: Article

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.

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Accepted/In Press date: 7 May 2018
e-pub ahead of print date: 6 July 2018

Identifiers

Local EPrints ID: 422841
URI: http://eprints.soton.ac.uk/id/eprint/422841
ISSN: 1932-6203
PURE UUID: eb089111-954a-4d2a-b98e-3f575a6dedcb
ORCID for Diana M. Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 06 Aug 2018 16:31
Last modified: 26 Nov 2021 07:07

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Contributors

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

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