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

被引：10

作者：

Earp, Madalene ^{[1
]}

Tyrer, Jonathan P. ^{[2
]}

Winham, Stacey J. ^{[1
]}

Lin, Hui-Yi ^{[3
,4
]}

Chornokur, Ganna ^{[5
]}

Dennis, Joe ^{[2
]}

Aben, Katja K. H. ^{[6
,7
]}

Anton-Culver, Hoda ^{[8
]}

Antonenkova, Natalia ^{[9
]}

Bandera, Elisa V. ^{[10
]}

Bean, Yukie T. ^{[11
,12
]}

Beckmann, Matthias W. ^{[13
]}

Bjorge, Line ^{[14
,15
]}

Bogdanova, Natalia ^{[16
]}

Brinton, Louise A. ^{[17
]}

Brooks-Wilson, Angela ^{[18
,19
]}

Bruinsma, Fiona ^{[20
]}

Bunker, Clareann H. ^{[21
]}

Butzow, Ralf ^{[22
,23
,24
]}

Campbell, Ian G. ^{[25
,26
,27
]}

Carty, Karen ^{[28
,29
]}

Chang-Claude, Jenny ^{[30
,31
]}

Cook, Linda S. ^{[32
]}

Cramer, Daniel W. ^{[33
,34
]}

Cunningham, Julie M. ^{[35
]}

Cybulski, Cezary ^{[36
]}

Dansonka-Mieszkowska, Agnieszka ^{[37
]}

Despierre, Evelyn ^{[38
,39
]}

Doherty, Jennifer A. ^{[40
,41
]}

Doerk, Thilo ^{[16
]}

du Bois, Andreas ^{[42
,43
]}

Duerst, Matthias ^{[44
]}

Easton, Douglas F. ^{[45
,46
]}

Eccles, Diana M. ^{[47
]}

Edwards, Robert P. ^{[48
]}

Ekici, Arif B. ^{[49
]}

Fasching, Peter A. ^{[13
,50
]}

Fridley, Brooke L. ^{[51
]}

Gentry-Maharaj, Aleksandra ^{[52
]}

Giles, Graham G. ^{[20
,53
]}

Glasspool, Rosalind ^{[28
]}

Goodman, Marc T. ^{[54
]}

Gronwald, Jacek ^{[36
]}

Harter, Philipp ^{[42
,43
]}

Hein, Alexander ^{[13
]}

Heitz, Florian ^{[42
,43
]}

Hildebrandt, Michelle A. T. ^{[55
]}

Hillemanns, Peter ^{[16
]}

Hogdall, Claus K. ^{[56
]}

Hogdall, Estrid ^{[57
,58
]}

机构：

[1] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[2] Univ Cambridge, Dept Oncol, Strangeways Res Lab, Cambridge, England

[3] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL USA

[4] Louisiana State Univ, Sch Publ Hlth, Hlth Sci Ctr, New Orleans, LA USA

[5] H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Dept Canc Epidemiol, Tampa, FL USA

[6] Netherlands Comprehens Canc Org, Utrecht, Netherlands

[7] Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, Nijmegen, Netherlands

[8] Univ Calif Irvine, Genet Epidemiol Res Inst, Sch Med, UCI Ctr Canc Genet Res & Prevent,Dept Epidemiol, Irvine, CA USA

[9] Byelorussian Inst Oncol & Med Radiol Aleksandrov, Minsk, BELARUS

[10] Rutgers Canc Inst New Jersey, Canc Prevent & Control, New Brunswick, NJ USA

[11] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA

[12] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[13] Univ Hosp Erlangen, Univ Breast Ctr Franconia, Dept Gynecol & Obstet, Erlangen, Germany

[14] Haukeland Hosp, Dept Gynecol & Obstet, Bergen, Norway

[15] Univ Bergen, Dept Clin Med, Ctr Canc Biomarkers, Bergen, Norway

[16] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany

[17] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[18] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada

[19] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada

[20] Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia

[21] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA

[22] Univ Helsinki, Dept Pathol, Cent Hosp, Helsinki, Finland

[23] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland

[24] Univ Helsinki, Cent Hosp, Helsinki, Finland

[25] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, Melbourne, Australia

[26] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia

[27] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia

[28] Beatson W Scotland Canc Ctr, CRUK Clin Trials Unit, Glasgow, Lanark, Scotland

[29] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow, Lanark, Scotland

[30] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[31] Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg, Hamburg, Germany

[32] Univ New Mexico, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA

[33] Brigham & Womens Hosp, Obstet & Gynecol Ctr, 75 Francis St, Boston, MA 02115 USA

[34] Harvard Med Sch, Boston, MA USA

[35] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[36] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland

[37] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Pathol, Warsaw, Poland

[38] Univ Hosp Leuven, Div Gynecol Oncol, Dept Obstet & Gynecol, Leuven, Belgium

[39] Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium

[40] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA

[41] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA

[42] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynaecol & Gynaecol Oncol, Wiesbaden, Germany

[43] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynaecol & Gynaecol Oncol, Essen, Germany

[44] Friedrich Schiller Univ, Dept Gynecol, Jena, Germany

[45] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England

[46] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England

[47] Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England

[48] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA

[49] Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Inst Human Genet, Erlangen, Germany

[50] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA

来源：

PLOS ONE | 2018年 / 13卷 / 07期

基金：

加拿大健康研究院; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; CARCINOMA;

D O I：

10.1371/journal.pone.0197561

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 bio-features 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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