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

Authors:
Dr Madalene Earp, PhD
Dr Madalene Earp, PhD
University of Calgary
Research Associate
Cancer genetics, palliative care
Calgary , Alberta | Canada
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

PLoS One 2018 6;13(7):e0197561. Epub 2018 Jul 6.

Division of Population Sciences, Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, United States of America.

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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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197561PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034790PMC

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December 2018
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