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

Publication ,  Journal Article
Earp, M; Tyrer, JP; Winham, SJ; Lin, H-Y; Chornokur, G; Dennis, J; Aben, KKH; Anton-Culver, H; Antonenkova, N; Bandera, EV; Bean, YT; Carty, K ...
Published in: PLoS One
2018

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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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2018

Volume

13

Issue

7

Start / End Page

e0197561

Location

United States

Related Subject Headings

  • Risk Factors
  • Rho Guanine Nucleotide Exchange Factors
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Monomeric GTP-Binding Proteins
  • Humans
  • Genotype
  • Genetic Predisposition to Disease
  • Genetic Association Studies
  • General Science & Technology
 

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Earp, M., Tyrer, J. P., Winham, S. J., Lin, H.-Y., Chornokur, G., Dennis, J., … Phelan, C. M. (2018). Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility. PLoS One, 13(7), e0197561. https://doi.org/10.1371/journal.pone.0197561
Earp, Madalene, Jonathan P. Tyrer, Stacey J. Winham, Hui-Yi Lin, Ganna Chornokur, Joe Dennis, Katja K. H. Aben, et al. “Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.PLoS One 13, no. 7 (2018): e0197561. https://doi.org/10.1371/journal.pone.0197561.
Earp M, Tyrer JP, Winham SJ, Lin H-Y, Chornokur G, Dennis J, et al. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility. PLoS One. 2018;13(7):e0197561.
Earp, Madalene, et al. “Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.PLoS One, vol. 13, no. 7, 2018, p. e0197561. Pubmed, doi:10.1371/journal.pone.0197561.
Earp M, Tyrer JP, Winham SJ, Lin H-Y, Chornokur G, Dennis J, Aben KKH, Anton-Culver H, Antonenkova N, Bandera EV, Bean YT, Beckmann MW, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bruinsma F, Bunker CH, Butzow R, Campbell IG, Carty K, Chang-Claude J, Cook LS, Cramer DW, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, Despierre E, Doherty JA, Dörk T, du Bois A, Dürst M, Easton DF, Eccles DM, Edwards RP, Ekici AB, Fasching PA, Fridley BL, Gentry-Maharaj A, Giles GG, Glasspool R, Goodman MT, Gronwald J, Harter P, Hein A, Heitz F, Hildebrandt MAT, Hillemanns P, Hogdall CK, Høgdall E, Hosono S, Iversen ES, Jakubowska A, Jensen A, Ji B-T, Jung AY, Karlan BY, Kellar M, Kiemeney LA, Kiong Lim B, Kjaer SK, Krakstad C, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lele S, Lester J, Levine DA, Li Z, Liang D, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LFAG, Matsuo K, McGuire V, McLaughlin JR, McNeish I, Menon U, Milne RL, Modugno F, Moysich KB, Ness RB, Nevanlinna H, Odunsi K, Olson SH, Orlow I, Orsulic S, Paul J, Pejovic T, Pelttari LM, Permuth JB, Pike MC, Poole EM, Rosen B, Rossing MA, Rothstein JH, Runnebaum IB, Rzepecka IK, Schernhammer E, Schwaab I, Shu X-O, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Spiewankiewicz B, Sucheston-Campbell L, Tangen IL, Teo S-H, Terry KL, Thompson PJ, Thomsen L, Tworoger SS, van Altena AM, Vergote I, Vestrheim Thomsen LC, Vierkant RA, Walsh CS, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Woo Y-L, Wu AH, Wu X, Xiang Y-B, Yang H, Zheng W, Ziogas A, Lee AW, Pearce CL, Berchuck A, Schildkraut JM, Ramus SJ, Monteiro ANA, Narod SA, Sellers TA, Gayther SA, Kelemen LE, Chenevix-Trench G, Risch HA, Pharoah PDP, Goode EL, Phelan CM. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility. PLoS One. 2018;13(7):e0197561.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2018

Volume

13

Issue

7

Start / End Page

e0197561

Location

United States

Related Subject Headings

  • Risk Factors
  • Rho Guanine Nucleotide Exchange Factors
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Monomeric GTP-Binding Proteins
  • Humans
  • Genotype
  • Genetic Predisposition to Disease
  • Genetic Association Studies
  • General Science & Technology