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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.

Type Journal
ISBN 1932-6203 (Electronic) 1932-6203 (Linking)
Authors Earp, M.; Tyrer, J. P.; Winham, S. J.; Lin, H. Y.; Chornokur, G.; Dennis, J.; Aben, K. K. H.; Anton-Culver, H.; Antonenkova, N.; Bandera, E. V.; Bean, Y. T.; Beckmann, M. W.; Bjorge, L.; Bogdanova, N.; Brinton, L. A.; Brooks-Wilson, A.; Bruinsma, F.; Bunker, C. H.; Butzow, R.; Campbell, I. G.; Carty, K.; Chang-Claude, J.; Cook, L. S.; Cramer, D. W.; Cunningham, J. M.; Cybulski, C.; Dansonka-Mieszkowska, A.; Despierre, E.; Doherty, J. A.; Dork, T.; du Bois, A.; Durst, M.; Easton, D. F.; Eccles, D. M.; Edwards, R. P.; Ekici, A. B.; Fasching, P. A.; Fridley, B. L.; Gentry-Maharaj, A.; Giles, G. G.; Glasspool, R.; Goodman, M. T.; Gronwald, J.; Harter, P.; Hein, A.; Heitz, F.; Hildebrandt, M. A. T.; Hillemanns, P.; Hogdall, C. K.; Hogdall, E.; Hosono, S.; Iversen, E. S.; Jakubowska, A.; Jensen, A.; Ji, B. T.; Jung, A. Y.; Karlan, B. Y.; Kellar, M.; Kiemeney, L. A.; Kiong Lim, B.; Kjaer, S. K.; Krakstad, C.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N. D.; Lele, S.; Lester, J.; Levine, D. A.; Li, Z.; Liang, D.; Lissowska, J.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, Lfag; Matsuo, K.; McGuire, V.; McLaughlin, J. R.; McNeish, I.; Menon, U.; Milne, R. L.; Modugno, F.; Moysich, K. B.; Ness, R. B.; Nevanlinna, H.; Odunsi, K.; Olson, S. H.; Orlow, I.; Orsulic, S.; Paul, J.; Pejovic, T.; Pelttari, L. M.; Permuth, J. B.; Pike, M. C.; Poole, E. M.; Rosen, B.; Rossing, M. A.; Rothstein, J. H.; Runnebaum, I. B., et al.
Publisher Name PLoS One
Published Date 2018-07-06
Published Volume 13
Published Issue 7
Published Pages e0197561
Status Always Electronic
DOI 10.1371/journal.pone.0197561
URL link to publisher's version
OpenAccess link to author's accepted manuscript version