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. 2018 Jul 6;13(7):e0197561.
doi: 10.1371/journal.pone.0197561. eCollection 2018.

Variants in Genes Encoding Small GTPases and Association With Epithelial Ovarian Cancer Susceptibility

Madalene Earp  1 Jonathan P Tyrer  2 Stacey J Winham  1 Hui-Yi Lin  3   4 Ganna Chornokur  5 Joe Dennis  2 Katja K H Aben  6   7 Hoda Anton-Culver  8 Natalia Antonenkova  9 Elisa V Bandera  10 Yukie T Bean  11   12 Matthias W Beckmann  13 Line Bjorge  14   15 Natalia Bogdanova  16 Louise A Brinton  17 Angela Brooks-Wilson  18   19 Fiona Bruinsma  20 Clareann H Bunker  21 Ralf Butzow  22   23 Ian G Campbell  24   25   26 Karen Carty  27   28 Jenny Chang-Claude  29   30 Linda S Cook  31 Daniel W Cramer  32 Julie M Cunningham  33 Cezary Cybulski  34 Agnieszka Dansonka-Mieszkowska  35 Evelyn Despierre  36 Jennifer A Doherty  37   38 Thilo Dörk  16 Andreas du Bois  39   40 Matthias Dürst  41 Douglas F Easton  42   43 Diana M Eccles  44 Robert P Edwards  45 Arif B Ekici  46 Peter A Fasching  13   47 Brooke L Fridley  48 Aleksandra Gentry-Maharaj  49 Graham G Giles  20   50 Rosalind Glasspool  27 Marc T Goodman  51 Jacek Gronwald  34 Philipp Harter  39   40 Alexander Hein  13 Florian Heitz  39   40 Michelle A T Hildebrandt  52 Peter Hillemanns  16 Claus K Hogdall  53 Estrid Høgdall  54   55 Satoyo Hosono  56 Edwin S Iversen  57 Anna Jakubowska  34 Allan Jensen  54 Bu-Tian Ji  17 Audrey Y Jung  29 Beth Y Karlan  58 Melissa Kellar  11   12 Lambertus A Kiemeney  7 Boon Kiong Lim  59 Susanne K Kjaer  54   60 Camilla Krakstad  14 Jolanta Kupryjanczyk  35 Diether Lambrechts  61   62 Sandrina Lambrechts  63 Nhu D Le  64 Shashi Lele  65 Jenny Lester  58 Douglas A Levine  66 Zheng Li  1   67 Dong Liang  68 Jolanta Lissowska  69 Karen Lu  70 Jan Lubinski  34 Lene Lundvall  53 Leon F A G Massuger  71 Keitaro Matsuo  56 Valerie McGuire  72 John R McLaughlin  73 Iain McNeish  73 Usha Menon  49 Roger L Milne  20   50 Francesmary Modugno  21   45   74 Kirsten B Moysich  65 Roberta B Ness  75 Heli Nevanlinna  23 Kunle Odunsi  76 Sara H Olson  77 Irene Orlow  77 Sandra Orsulic  58 James Paul  27 Tanja Pejovic  11   12 Liisa M Pelttari  23 Jenny B Permuth  5 Malcolm C Pike  77 Elizabeth M Poole  78   79 Barry Rosen  80 Mary Anne Rossing  37 Joseph H Rothstein  81 Ingo B Runnebaum  41 Iwona K Rzepecka  35 Eva Schernhammer  78   79 Ira Schwaab  82 Xiao-Ou Shu  83 Yurii B Shvetsov  84 Nadeem Siddiqui  84 Weiva Sieh  81 Honglin Song  4 Melissa C Southey  26 Beata Spiewankiewicz  85 Lara Sucheston-Campbell  65 Ingvild L Tangen  14 Soo-Hwang Teo  86   87 Kathryn L Terry  79   88 Pamela J Thompson  51 Lotte Thomsen  89 Shelley S Tworoger  5   78   79 Anne M van Altena  90 Ignace Vergote  63 Liv Cecilie Vestrheim Thomsen  14 Robert A Vierkant  1 Christine S Walsh  58 Shan Wang-Gohrke  91 Nicolas Wentzensen  17 Alice S Whittemore  92 Kristine G Wicklund  37 Lynne R Wilkens  84 Yin-Ling Woo  59   93 Anna H Wu  94 Xifeng Wu  52 Yong-Bing Xiang  95 Hannah Yang  17 Wei Zheng  96 Argyrios Ziogas  8 Alice W Lee  97 Celeste L Pearce  88 Andrew Berchuck  98 Joellen M Schildkraut  99 Susan J Ramus  100   101 Alvaro N A Monteiro  5 Steven A Narod  102 Thomas A Sellers  5 Simon A Gayther  103 Linda E Kelemen  104 Georgia Chenevix-Trench  105 Harvey A Risch  106 Paul D P Pharoah  2   107 Ellen L Goode  1 Catherine M Phelan  5
Affiliations
Free PMC article

Variants in Genes Encoding Small GTPases and Association With Epithelial Ovarian Cancer Susceptibility

Madalene Earp et al. PLoS One. .
Free PMC 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.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Association of rs2256787 in the ARHGEF10L gene with invasive endometrioid EOC risk by study site and combined.
Squares represent the estimated per-allele odds ratio (OR) and are proportional to sample size for each study; lines indicate its 95% confidence interval (CI); source indicates contributing study;[11] MAF, control minor allele frequency; PVal, per-allele p-value adjusted for age, site, and principal components to account for residual differences in European ancestry.

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