TY - JOUR

T1 - Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

AU - Earp, Madalene

AU - Tyrer, Jonathan P

AU - Winham, Stacey J

AU - Lin, Hui-Yi

AU - Chornokur, Ganna

AU - Dennis, Joe

AU - Aben, Katja K H

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia

AU - Bandera, Elisa V

AU - Bean, Yukie T

AU - Beckmann, Matthias W

AU - Bjorge, Line

AU - Bogdanova, Natalia

AU - Brinton, Louise A

AU - Brooks-Wilson, Angela

AU - Bruinsma, Fiona

AU - Bunker, Clareann H

AU - Butzow, Ralf

AU - Campbell, Ian G

AU - Carty, Karen

AU - Chang-Claude, Jenny

AU - Cook, Linda S

AU - Cramer, Daniel W

AU - Cunningham, Julie M

AU - Cybulski, Cezary

AU - Dansonka-Mieszkowska, Agnieszka

AU - Despierre, Evelyn

AU - Doherty, Jennifer A

AU - Dörk, Thilo

AU - du Bois, Andreas

AU - Dürst, Matthias

AU - Easton, Douglas F

AU - Eccles, Diana M

AU - Edwards, Robert P

AU - Ekici, Arif B

AU - Fasching, Peter A

AU - Fridley, Brooke L

AU - Gentry-Maharaj, Aleksandra

AU - Giles, Graham G

AU - Glasspool, Rosalind

AU - Goodman, Marc T

AU - Gronwald, Jacek

AU - Harter, Philipp

AU - Hein, Alexander

AU - Heitz, Florian

AU - Hildebrandt, Michelle A T

AU - Hillemanns, Peter

AU - Hogdall, Claus K

AU - Høgdall, Estrid

AU - Hosono, Satoyo

AU - Iversen, Edwin S

AU - Jakubowska, Anna

AU - Jensen, Allan

AU - Ji, Bu-Tian

AU - Jung, Audrey Y

AU - Karlan, Beth Y

AU - Kellar, Melissa

AU - Kiemeney, Lambertus A

AU - Kiong Lim, Boon

AU - Kjaer, Susanne K

AU - Krakstad, Camilla

AU - Kupryjanczyk, Jolanta

AU - Lambrechts, Diether

AU - Lambrechts, Sandrina

AU - Le, Nhu D

AU - Lele, Shashi

AU - Lester, Jenny

AU - Levine, Douglas A

AU - Li, Zheng

AU - Liang, Dong

AU - Lissowska, Jolanta

AU - Lu, Karen

AU - Lubinski, Jan

AU - Lundvall, Lene

AU - Massuger, Leon F A G

AU - Matsuo, Keitaro

AU - McGuire, Valerie

AU - McLaughlin, John R

AU - McNeish, Iain

AU - Menon, Usha

AU - Milne, Roger L

AU - Modugno, Francesmary

AU - Moysich, Kirsten B

AU - Ness, Roberta B

AU - Nevanlinna, Heli

AU - Odunsi, Kunle

AU - Olson, Sara H

AU - Orlow, Irene

AU - Orsulic, Sandra

AU - Paul, James

AU - Pejovic, Tanja

AU - Pelttari, Liisa M

AU - Permuth, Jenny B

AU - Pike, Malcolm C

AU - Poole, Elizabeth M

AU - Rosen, Barry

AU - Rossing, Mary Anne

AU - Rothstein, Joseph H

AU - Runnebaum, Ingo B

AU - Rzepecka, Iwona K

AU - Schernhammer, Eva

AU - Schwaab, Ira

AU - Shu, Xiao-Ou

AU - Shvetsov, Yurii B

AU - Siddiqui, Nadeem

AU - Sieh, Weiva

AU - Song, Honglin

AU - Southey, Melissa C

AU - Spiewankiewicz, Beata

AU - Sucheston-Campbell, Lara

AU - Tangen, Ingvild L

AU - Teo, Soo-Hwang

AU - Terry, Kathryn L

AU - Thompson, Pamela J

AU - Thomsen, Lotte

AU - Tworoger, Shelley S

AU - van Altena, Anne M

AU - Vergote, Ignace

AU - Vestrheim Thomsen, Liv Cecilie

AU - Vierkant, Robert A

AU - Walsh, Christine S

AU - Wang-Gohrke, Shan

AU - Wentzensen, Nicolas

AU - Whittemore, Alice S

AU - Wicklund, Kristine G

AU - Wilkens, Lynne R

AU - Woo, Yin-Ling

AU - Wu, Anna H

AU - Wu, Xifeng

AU - Xiang, Yong-Bing

AU - Yang, Hannah

AU - Zheng, Wei

AU - Ziogas, Argyrios

AU - Lee, Alice W

AU - Pearce, Celeste L

AU - Berchuck, Andrew

AU - Schildkraut, Joellen M

AU - Ramus, Susan J

AU - Monteiro, Alvaro N A

AU - Narod, Steven A

AU - Sellers, Thomas A

AU - Gayther, Simon A

AU - Kelemen, Linda E

AU - Chenevix-Trench, Georgia

AU - Risch, Harvey A

AU - Pharoah, Paul D P

AU - Goode, Ellen L

AU - Phelan, Catherine M

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - A Kinase Anchor Proteins/genetics

KW - Carcinoma, Ovarian Epithelial/genetics

KW - Female

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Humans

KW - Monomeric GTP-Binding Proteins/genetics

KW - Polymorphism, Single Nucleotide/genetics

KW - Quantitative Trait Loci/genetics

KW - Rho Guanine Nucleotide Exchange Factors/genetics

KW - Risk Factors

U2 - 10.1371/journal.pone.0197561

DO - 10.1371/journal.pone.0197561

M3 - Journal article

C2 - 29979793

VL - 13

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 7

M1 - e0197561

ER -