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

Madalene Earp; 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

doi:10.1371/journal.pone.0197561

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

Madalene Earp, 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 CampbellKaren 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

Department of Clinical Medicine

8 Citations (Scopus)

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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.

Original language	English
Article number	e0197561
Journal	PLoS ONE
Volume	13
Issue number	7
Number of pages	13
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0197561
Publication status	Published - Jul 2018

Keywords

A Kinase Anchor Proteins/genetics
Carcinoma, Ovarian Epithelial/genetics
Female
Genetic Association Studies
Genetic Predisposition to Disease
Genotype
Humans
Monomeric GTP-Binding Proteins/genetics
Polymorphism, Single Nucleotide/genetics
Quantitative Trait Loci/genetics
Rho Guanine Nucleotide Exchange Factors/genetics
Risk Factors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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journal.pone.0197561Final published version, 2.47 MBLicence: CC BY

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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., ... 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, 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 2018, 'Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility', PLoS ONE, vol. 13, no. 7, e0197561. https://doi.org/10.1371/journal.pone.0197561

@article{8047ec5ce89a4ec799e841189d700a47,

title = "Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility",

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.",

keywords = "A Kinase Anchor Proteins/genetics, Carcinoma, Ovarian Epithelial/genetics, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Monomeric GTP-Binding Proteins/genetics, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Rho Guanine Nucleotide Exchange Factors/genetics, Risk Factors",

author = "Madalene Earp and Tyrer, {Jonathan P} and Winham, {Stacey J} and Hui-Yi Lin and Ganna Chornokur and Joe Dennis and Aben, {Katja K H} and Hoda Anton-Culver and Natalia Antonenkova and Bandera, {Elisa V} and Bean, {Yukie T} and Beckmann, {Matthias W} and Line Bjorge and Natalia Bogdanova and Brinton, {Louise A} and Angela Brooks-Wilson and Fiona Bruinsma and Bunker, {Clareann H} and Ralf Butzow and Campbell, {Ian G} and Karen Carty and Jenny Chang-Claude and Cook, {Linda S} and Cramer, {Daniel W} and Cunningham, {Julie M} and Cezary Cybulski and Agnieszka Dansonka-Mieszkowska and Evelyn Despierre and Doherty, {Jennifer A} and Thilo D{\"o}rk and {du Bois}, Andreas and Matthias D{\"u}rst and Easton, {Douglas F} and Eccles, {Diana M} and Edwards, {Robert P} and Ekici, {Arif B} and Fasching, {Peter A} and Fridley, {Brooke L} and Aleksandra Gentry-Maharaj and Giles, {Graham G} and Rosalind Glasspool and Goodman, {Marc T} and Jacek Gronwald and Philipp Harter and Alexander Hein and Florian Heitz and Hildebrandt, {Michelle A T} and Peter Hillemanns and Hogdall, {Claus K} and Estrid H{\o}gdall and Satoyo Hosono and Iversen, {Edwin S} and Anna Jakubowska and Allan Jensen and Bu-Tian Ji and Jung, {Audrey Y} and Karlan, {Beth Y} and Melissa Kellar and Kiemeney, {Lambertus A} and {Kiong Lim}, Boon and Kjaer, {Susanne K} and Camilla Krakstad and Jolanta Kupryjanczyk and Diether Lambrechts and Sandrina Lambrechts and Le, {Nhu D} and Shashi Lele and Jenny Lester and Levine, {Douglas A} and Zheng Li and Dong Liang and Jolanta Lissowska and Karen Lu and Jan Lubinski and Lene Lundvall and Massuger, {Leon F A G} and Keitaro Matsuo and Valerie McGuire and McLaughlin, {John R} and Iain McNeish and Usha Menon and Milne, {Roger L} and Francesmary Modugno and Moysich, {Kirsten B} and Ness, {Roberta B} and Heli Nevanlinna and Kunle Odunsi and Olson, {Sara H} and Irene Orlow and Sandra Orsulic and James Paul and Tanja Pejovic and Pelttari, {Liisa M} and Permuth, {Jenny B} and Pike, {Malcolm C} and Poole, {Elizabeth M} and Barry Rosen and Rossing, {Mary Anne} and Rothstein, {Joseph H} and Runnebaum, {Ingo B} and Rzepecka, {Iwona K} and Eva Schernhammer and Ira Schwaab and Xiao-Ou Shu and Shvetsov, {Yurii B} and Nadeem Siddiqui and Weiva Sieh and Honglin Song and Southey, {Melissa C} and Beata Spiewankiewicz and Lara Sucheston-Campbell and Tangen, {Ingvild L} and Soo-Hwang Teo and Terry, {Kathryn L} and Thompson, {Pamela J} and Lotte Thomsen and Tworoger, {Shelley S} and {van Altena}, {Anne M} and Ignace Vergote and {Vestrheim Thomsen}, {Liv Cecilie} and Vierkant, {Robert A} and Walsh, {Christine S} and Shan Wang-Gohrke and Nicolas Wentzensen and Whittemore, {Alice S} and Wicklund, {Kristine G} and Wilkens, {Lynne R} and Yin-Ling Woo and Wu, {Anna H} and Xifeng Wu and Yong-Bing Xiang and Hannah Yang and Wei Zheng and Argyrios Ziogas and Lee, {Alice W} and Pearce, {Celeste L} and Andrew Berchuck and Schildkraut, {Joellen M} and Ramus, {Susan J} and Monteiro, {Alvaro N A} and Narod, {Steven A} and Sellers, {Thomas A} and Gayther, {Simon A} and Kelemen, {Linda E} and Georgia Chenevix-Trench and Risch, {Harvey A} and Pharoah, {Paul D P} and Goode, {Ellen L} and Phelan, {Catherine M}",

year = "2018",

month = jul,

doi = "10.1371/journal.pone.0197561",

language = "English",

volume = "13",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "7",

}

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 - 2018/7

Y1 - 2018/7

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

SN - 1932-6203

VL - 13

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 7

M1 - e0197561

ER -

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

Abstract

Keywords

UN SDGs

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