A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk

Yingchang Lu; Alicia Beeghly-Fadiel; Lang Wu; Xingyi Guo; Bingshan Li; Joellen M. Schildkraut; Hae Kyung Im; Yian A. Chen; Jennifer B. Permuth; Brett M. Reid; Jamie K. Teer; Kirsten B. Moysich; Irene L. Andrulis; Hoda Anton-Culver; Banu K. Arun; Elisa V. Bandera; Rosa B. Barkardottir; Daniel R. Barnes; Javier Benitez; Line Bjorge; James Brenton; Ralf Butzow; Trinidad Caldes; Maria A. Caligo; Ian Campbell; Jenny Chang-Claude; Kathleen B.M. Claes; Fergus J. Couch; Daniel W. Cramer; Mary B. Daly; Anna DeFazio; Joe Dennis; Orland Diez; Susan M. Domchek; Thilo D rk; Douglas F. Easton; Diana M. Eccles; Peter A. Fasching; Ren e.T. Fortner; George Fountzilas; Eitan Friedman; Patricia A. Ganz; Judy Garber; Graham G. Giles; Andrew K. Godwin; David E. Goldgar; Marc T. Goodman; Mark H. Greene; Jacek Gronwald; Ute Hamann; Florian Heitz; Michelle A.T. Hildebrandt; Claus K. Høgdall; Antoinette Hollestelle; Peter J. Hulick; David G. Huntsman; Evgeny N. Imyanitov; Claudine Isaacs; Anna Jakubowska; Paul James; Beth Y. Karlan; Linda E. Kelemen; Lambertus A. Kiemeney; Susanne K. Kjaer; Ava Kwong; Nhu D. Le; Goska Leslie; Fabienne Lesueur; Douglas A. Levine; Amalia Mattiello; Taymaa May; Lesley McGuffog; Iain A. McNeish; Melissa A. Merritt; Francesmary Modugno; Marco Montagna; Susan L. Neuhausen; Heli Nevanlinna; Finn C. Nielsen; Liene Nikitina-Zake; Robert L. Nussbaum; Kenneth Offit; Edith Olah; Olufunmilayo I. Olopade; Sara H. Olson; H. kan Olsson; Ana Osorio; Sue K. Park; Michael T. Parsons; Petra H.M. Peeters; Tanja Pejovic; Paolo Peterlongo; Catherine M. Phelan; Miquel Angel Pujana; Susan J. Ramus; Gad Rennert; Harvey Risch; Gustavo C. Rodriguez; Cristina Rodríguez-Antona; Isabelle Romieu; Matti A. Rookus; Mary Anne Rossing; Iwona K. Rzepecka; Dale P. Sandler; Rita K. Schmutzler; Veronica W. Setiawan; Priyanka Sharma; Weiva Sieh; Jacques Simard; Christian F. Singer; Honglin Song; Melissa C. Southey; Amanda B. Spurdle; Rebecca Sutphen; Anthony J. Swerdlow; Manuel R. Teixeira; Soo H. Teo; Mads Thomassen; Marc Tischkowitz; Amanda E. Toland; Antonia Trichopoulou; Nadine Tung; Shelley S. Tworoger; Elizabeth J. Van Rensburg; Adriaan Vanderstichele; Ana Vega; Digna Velez Edwards; Penelope M. Webb; Jeffrey N. Weitzel; Nicolas Wentzensen; Emily White; Alicja Wolk; Anna H. Wu; Drakoulis Yannoukakos; Kristin K. Zorn; Simon A. Gayther; Antonis C. Antoniou; Andrew Berchuck; Ellen L. Goode; Georgia Chenevix-Trench; Thomas A. Sellers; Paul D.P. Pharoah; Wei Zheng; Jirong Long

doi:10.1158/0008-5472.CAN-18-0951

A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk

Yingchang Lu, Alicia Beeghly-Fadiel, Lang Wu, Xingyi Guo, Bingshan Li, Joellen M. Schildkraut, Hae Kyung Im, Yian A. Chen, Jennifer B. Permuth, Brett M. Reid, Jamie K. Teer, Kirsten B. Moysich, Irene L. Andrulis, Hoda Anton-Culver, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Javier Benitez, Line BjorgeJames Brenton, Ralf Butzow, Trinidad Caldes, Maria A. Caligo, Ian Campbell, Jenny Chang-Claude, Kathleen B.M. Claes, Fergus J. Couch, Daniel W. Cramer, Mary B. Daly, Anna DeFazio, Joe Dennis, Orland Diez, Susan M. Domchek, Thilo D rk, Douglas F. Easton, Diana M. Eccles, Peter A. Fasching, Ren e.T. Fortner, George Fountzilas, Eitan Friedman, Patricia A. Ganz, Judy Garber, Graham G. Giles, Andrew K. Godwin, David E. Goldgar, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Ute Hamann, Florian Heitz, Michelle A.T. Hildebrandt, Claus K. Høgdall, Antoinette Hollestelle, Peter J. Hulick, David G. Huntsman, Evgeny N. Imyanitov, Claudine Isaacs, Anna Jakubowska, Paul James, Beth Y. Karlan, Linda E. Kelemen, Lambertus A. Kiemeney, Susanne K. Kjaer, Ava Kwong, Nhu D. Le, Goska Leslie, Fabienne Lesueur, Douglas A. Levine, Amalia Mattiello, Taymaa May, Lesley McGuffog, Iain A. McNeish, Melissa A. Merritt, Francesmary Modugno, Marco Montagna, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Liene Nikitina-Zake, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Sara H. Olson, H. kan Olsson, Ana Osorio, Sue K. Park, Michael T. Parsons, Petra H.M. Peeters, Tanja Pejovic, Paolo Peterlongo, Catherine M. Phelan, Miquel Angel Pujana, Susan J. Ramus, Gad Rennert, Harvey Risch, Gustavo C. Rodriguez, Cristina Rodríguez-Antona, Isabelle Romieu, Matti A. Rookus, Mary Anne Rossing, Iwona K. Rzepecka, Dale P. Sandler, Rita K. Schmutzler, Veronica W. Setiawan, Priyanka Sharma, Weiva Sieh, Jacques Simard, Christian F. Singer, Honglin Song, Melissa C. Southey, Amanda B. Spurdle, Rebecca Sutphen, Anthony J. Swerdlow, Manuel R. Teixeira, Soo H. Teo, Mads Thomassen, Marc Tischkowitz, Amanda E. Toland, Antonia Trichopoulou, Nadine Tung, Shelley S. Tworoger, Elizabeth J. Van Rensburg, Adriaan Vanderstichele, Ana Vega, Digna Velez Edwards, Penelope M. Webb, Jeffrey N. Weitzel, Nicolas Wentzensen, Emily White, Alicja Wolk, Anna H. Wu, Drakoulis Yannoukakos, Kristin K. Zorn, Simon A. Gayther, Antonis C. Antoniou, Andrew Berchuck, Ellen L. Goode, Georgia Chenevix-Trench, Thomas A. Sellers, Paul D.P. Pharoah, Wei Zheng, Jirong Long

Research output: Contribution to journal › Article › peer-review

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Abstract

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 10 ⁶ , we identified 35 genes, including FZD4 at 11q14.2 (Z ¼ 5.08, P ¼ 3.83 10 ⁷ , the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 10 ³ ). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.

Original language	English (US)
Pages (from-to)	5419-5430
Number of pages	12
Journal	Cancer Research
Volume	78
Issue number	18
DOIs	https://doi.org/10.1158/0008-5472.CAN-18-0951
State	Published - Sep 15 2018

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

Access to Document

10.1158/0008-5472.CAN-18-0951

Cite this

Lu, Y., Beeghly-Fadiel, A., Wu, L., Guo, X., Li, B., Schildkraut, J. M., Im, H. K., Chen, Y. A., Permuth, J. B., Reid, B. M., Teer, J. K., Moysich, K. B., Andrulis, I. L., Anton-Culver, H., Arun, B. K., Bandera, E. V., Barkardottir, R. B., Barnes, D. R., Benitez, J., ... Long, J. (2018). A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk. Cancer Research, 78(18), 5419-5430. https://doi.org/10.1158/0008-5472.CAN-18-0951

@article{7ae27c35b2284f3b8dd5338cac112acc,

title = "A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk",

abstract = " Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 10 6 , we identified 35 genes, including FZD4 at 11q14.2 (Z ¼ 5.08, P ¼ 3.83 10 7 , the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 10 3 ). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.",

author = "Yingchang Lu and Alicia Beeghly-Fadiel and Lang Wu and Xingyi Guo and Bingshan Li and Schildkraut, {Joellen M.} and Im, {Hae Kyung} and Chen, {Yian A.} and Permuth, {Jennifer B.} and Reid, {Brett M.} and Teer, {Jamie K.} and Moysich, {Kirsten B.} and Andrulis, {Irene L.} and Hoda Anton-Culver and Arun, {Banu K.} and Bandera, {Elisa V.} and Barkardottir, {Rosa B.} and Barnes, {Daniel R.} and Javier Benitez and Line Bjorge and James Brenton and Ralf Butzow and Trinidad Caldes and Caligo, {Maria A.} and Ian Campbell and Jenny Chang-Claude and Claes, {Kathleen B.M.} and Couch, {Fergus J.} and Cramer, {Daniel W.} and Daly, {Mary B.} and Anna DeFazio and Joe Dennis and Orland Diez and Domchek, {Susan M.} and {D rk}, Thilo and Easton, {Douglas F.} and Eccles, {Diana M.} and Fasching, {Peter A.} and Fortner, {Ren e.T.} and George Fountzilas and Eitan Friedman and Ganz, {Patricia A.} and Judy Garber and Giles, {Graham G.} and Godwin, {Andrew K.} and Goldgar, {David E.} and Goodman, {Marc T.} and Greene, {Mark H.} and Jacek Gronwald and Ute Hamann and Florian Heitz and Hildebrandt, {Michelle A.T.} and H{\o}gdall, {Claus K.} and Antoinette Hollestelle and Hulick, {Peter J.} and Huntsman, {David G.} and Imyanitov, {Evgeny N.} and Claudine Isaacs and Anna Jakubowska and Paul James and Karlan, {Beth Y.} and Kelemen, {Linda E.} and Kiemeney, {Lambertus A.} and Kjaer, {Susanne K.} and Ava Kwong and Le, {Nhu D.} and Goska Leslie and Fabienne Lesueur and Levine, {Douglas A.} and Amalia Mattiello and Taymaa May and Lesley McGuffog and McNeish, {Iain A.} and Merritt, {Melissa A.} and Francesmary Modugno and Marco Montagna and Neuhausen, {Susan L.} and Heli Nevanlinna and Nielsen, {Finn C.} and Liene Nikitina-Zake and Nussbaum, {Robert L.} and Kenneth Offit and Edith Olah and Olopade, {Olufunmilayo I.} and Olson, {Sara H.} and Olsson, {H. kan} and Ana Osorio and Park, {Sue K.} and Parsons, {Michael T.} and Peeters, {Petra H.M.} and Tanja Pejovic and Paolo Peterlongo and Phelan, {Catherine M.} and Pujana, {Miquel Angel} and Ramus, {Susan J.} and Gad Rennert and Harvey Risch and Rodriguez, {Gustavo C.} and Cristina Rodr{\'i}guez-Antona and Isabelle Romieu and Rookus, {Matti A.} and Rossing, {Mary Anne} and Rzepecka, {Iwona K.} and Sandler, {Dale P.} and Schmutzler, {Rita K.} and Setiawan, {Veronica W.} and Priyanka Sharma and Weiva Sieh and Jacques Simard and Singer, {Christian F.} and Honglin Song and Southey, {Melissa C.} and Spurdle, {Amanda B.} and Rebecca Sutphen and Swerdlow, {Anthony J.} and Teixeira, {Manuel R.} and Teo, {Soo H.} and Mads Thomassen and Marc Tischkowitz and Toland, {Amanda E.} and Antonia Trichopoulou and Nadine Tung and Tworoger, {Shelley S.} and {Van Rensburg}, {Elizabeth J.} and Adriaan Vanderstichele and Ana Vega and Edwards, {Digna Velez} and Webb, {Penelope M.} and Weitzel, {Jeffrey N.} and Nicolas Wentzensen and Emily White and Alicja Wolk and Wu, {Anna H.} and Drakoulis Yannoukakos and Zorn, {Kristin K.} and Gayther, {Simon A.} and Antoniou, {Antonis C.} and Andrew Berchuck and Goode, {Ellen L.} and Georgia Chenevix-Trench and Sellers, {Thomas A.} and Pharoah, {Paul D.P.} and Wei Zheng and Jirong Long",

note = "Funding Information: The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium that was funded by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The OCAC OncoArray genotyping project was funded through grants from the NIH [U19-CA148112 (to T.A. Sellers), R01-CA149429 (to C.M. Phelan), and R01-CA058598 (to M.T. Goodman); Canadian Institutes of Health Research (MOP-86727 (to L.E. Kelemen)] and the Ovarian Cancer Research Fund (to A. Berchuck). The COGS project was funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). Funding for individual studies: AAS: NIH (RO1-CA142081); AOV: The Canadian Institutes for Health Research (MOP-86727); AUS: The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia (199600, 400413 and 400281), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia (Multi-State Applications 191, 211, and 182). The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation; BAV: ELAN Funds of the University of Erlangen-Nuremberg; BEL: National Kankerplan; BGS: Breast Cancer Now, Institute of Cancer Research; BVU: Vanderbilt CTSA grant from the National Institutes of Health (NIH)/ National Center for Advancing Translational Sciences (NCATS) (ULTR000445); CAM: National Institutes of Health Research Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre; CHA: Innovative Research Team in University (PCSIRT) in China (IRT1076); CNI: Instituto de Salud Carlos III (PI 12/01319); Ministerio de Econom{\'i}a y Competitividad (SAF2012); COE: Department of Defense (W81XWH-11-2-0131); CON: National Institutes of Health (R01-CA063678, R01-CA074850; R01-CA080742); DKE: Ovarian Cancer Research Fund and National Institutes of Health 1R01CA211574 (J.M. Schildkraut); DOV: National Institutes of Health R01-CA112523 and R01-CA87538; EMC: Dutch Cancer Society (EMC 2014-6699); EPC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G{\'e}n{\'e}rale de l'Education Nationale, Institut National de la Sant{\'e}et de la Recherche M{\'e}dicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Funding Information: Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andaluc{\'i}a, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Ska°ne and V€asterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom); GER: German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ); GRC: This research has been co-financed by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program {"}Education and Lifelong Learning{"} of the National Strategic Reference Frame-work (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund; GRR: Roswell Park Cancer Institute Alliance Foundation, P30 CA016056; HAW: U.S. National Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001); HJO: Intramural funding; Rudolf-Bartling Foundation; HMO: Intramural funding; Rudolf-Bartling Foundation; HOC: Helsinki University Research Fund; HOP: Department of Defense (DAMD17-02-1-0669) and NCI (K07-CA080668, R01-CA95023, P50-CA159981 MO1-RR000056 R01-CA126841); HUO: Intramural funding; Rudolf-Bartling Foundation; JGO: JSPS KAKENHI grant; JPN: Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare; KRA: This study (Ko-EVE) was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 0920010); LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; LUN: ERC-2011-AdG 294576-risk factors cancer, Swedish Cancer Society, Swedish Research Council, Beta Kamprad Foundation; MAC: NIH (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Fraternal Order of Eagles; MAL: Funding for this study was provided by research grant R01-CA61107 from the National Cancer Institute, Bethesda, MD, research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project; MAS: Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; MAY: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MCC: Cancer Council Victoria, National Health and Medical Research Council of Australia (NHMRC) grants number 209057, 251533, 396414, and 504715; MDA: DOD Ovarian Cancer Research Program (W81XWH-07-0449); MEC: NIH (CA54281, CA164973, CA63464); MOF: Moffitt Cancer Center, Merck Pharmaceuticals, the state of Florida, Hillsborough County, and the city of Tampa; NCO: National Institutes of Health (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802; NHS: UM1 CA186107, P01 CA87969, R01 CA49449, R01-CA67262, UM1 CA176726; NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, P30-CA072720, and P30-CA008748) and the Cancer Institute of New Jersey; NOR: Helse Vest, The Norwegian Cancer Society, The Research Council of Norway; NTH: Radboud University Medical Centre; OPL: National Health and Medical Research Council (NHMRC) of Australia (APP1025142) and Brisbane Women's Club; ORE: OHSU Foundation; OVA: This work was supported by Canadian Institutes of Health Research grant (MOP-86727) and by NIH/NCI 1 R01CA160669-01A1; PLC: Intramural Research Program of the National Cancer Institute; POC: Pomeranian Medical University; POL: Intramural Research Program of the National Cancer Institute; PVD: Canadian Cancer Society and Cancer Research Society GRePEC Program; RBH: National Health and Medical Research Council of Australia; RMH: Cancer Research UK, Royal Marsden Hospital; RPC: National Institute of Health (P50 CA159981, R01CA126841); SEA: Cancer Research UK (C490/A10119 C490/ A10124); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; SIS: NIH, National Institute of Environmental Health Sciences, Z01 ES044005 and Z01-ES049033; SMC: The Swedish Research Council; SON: National Health Research and Development Program, Health Canada, grant 6613-1415-53; SRO: Cancer Research UK (C536/A13086, C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589); STA: NIH grants U01 CA71966 and U01 CA69417; SWE: Swedish Cancer foundation, WeCanCureCancer and a°rKampMotCancer foundation; SWH: NIH (NCI) grant R37-CA070867; TBO: National Institutes of Health (R01-CA106414-A2), American Cancer Society (CRTG-00-196-01-CCE), Department of Defense (DAMD17-98-1-8659), Celma Mastery Ovarian Cancer Foundation; TOR: NIH grants R01 CA063678 and R01 CA063682; UCI: NIH R01-CA058860 and the Lon V Smith Foundation grant LVS-39420; UHN: Princess Margaret Cancer Centre Foundation-Bridge for the Cure; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre; UKR: Cancer Research UK (C490/A6187), UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; USC: P01CA17054, P30CA14089, R01CA61132, N01PC67010, R03CA113148, R03CA115195, N01CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200); VAN: BC Cancer Foundation, VGH & UBC Hospital Foundation; VTL: NIH K05-CA154337; WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 & ID 628903. Cancer Institute NSW Grants 12/RIG/ 1-17 & 15/RIG/1-16; WOC: National Science Centren (N N301 5645 40). The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. We are grateful to the family and friends of Kathryn Sladek Smith for their generous support of the Ovarian Cancer Association Consortium through their donations to the Ovarian Cancer Research Fund. The OncoArray and COGS genotyping projects would not have been possible without the contributions of the following: Per Hall (COGS); Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Marjorie J. Riggan (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Jonathan P. Tyrer, Siddhartha Kar, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissi{\`e}re and Frederic Robidoux and the staff of the McGill University and G{\'e}nome Qu{\'e}bec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. We pay special tribute to the contribution of Professor Brian Henderson to the GAME-ON consortium and to Olga M. Sinilnikova for her contribution to CIMBA and for her part in the initiation and coordination of GEMO until she sadly passed away on the 30th June 2014. We thank the study participants, doctors, nurses, clinical and scientific collaborators, health care providers and health information sources who have contributed to the many studies contributing to this manuscript. Funding Information: Acknowledgements for individual studies: AOV: We thank Jennifer Koziak, Mie Konno, Michelle Darago, Faye Chambers and the Tom Baker Cancer Centre Translational Laboratories; AUS: The AOCS also acknowledges the cooperation of the participating institutions in Australia and acknowledges the contribution of the study nurses, research assistants and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www. aocstudy.org.We would like tothankallofthewomen who participated inthese research programs; BEL: We would like to thank Gilian Peuteman, Thomas Van Brussel, Annick Van den Broeck and Joke De Roover for technical assistance; BGS: The BGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. We thank the Study staff, study participants, doctors, nurses, health care providers and health information sources who have contributed to the study; BVU: The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH; CAM: This work was supported by Cancer Research UK; the University of Cambridge; National Institute for Health Research Cambridge Biomedical Research Centre; CHA: Innovative Research Team in University (PCSIRT) in China (IRT1076); CHN: To thank all members of Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital and Department of Molecular Biology, Hebei Medical University, Fourth Hospital; COE: Gynecologic Cancer Center of Excellence (W81XWH-11-2-0131); CON: The cooperation of the 32 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. This study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in this study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data; DKE: OCRF; EPC: To thank Funding Information: all members and investigators of the Rotterdam Ovarian Cancer Study. Dutch Cancer Society (EMC 2014-6699); GER: The German Ovarian Cancer Study (GER) thank Ursula Eilber for competent technical assistance; HOC: The study was supported by the Helsinki University Research Fund; JGO: JSPS KAKENHI grant; KRA: This study (Ko-EVE) was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 0920010); LUN: ERC -2011-AdG, Swedish Cancer Society, Swedish Research Council; MAS: We would like to thank Famida Zulkifli and Ms Moey for assistance in patient recruitment, data collection and sample preparation. The Malaysian Ovarian Cancer Genetic Study is funded by research grants from the Malaysian Ministry of Higher Education (UM.C/HIR/MOHE/06) and charitable funding from Cancer Research Initiatives Foundation; MCC: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database; MOF: the Total Cancer Care Protocol and the Collaborative Data Services and Tissue Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292), Merck Pharmaceuticals and the state of Florida; NHS: The NHS/NHSII studies thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY; NJO: L. Paddock, M. King, U. Chandran, A. Samoila, and Y. Bensman; OPL: Members of the OPAL Study Group (http://opalstudy.qimrberghofer.edu.au/); RPC: National Institute of Health (P50 CA159981, R01CA126841); SEA: SEARCH Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",

year = "2018",

month = sep,

day = "15",

doi = "10.1158/0008-5472.CAN-18-0951",

language = "English (US)",

volume = "78",

pages = "5419--5430",

journal = "Cancer Research",

issn = "0008-5472",

number = "18",

}

Lu, Y, Beeghly-Fadiel, A, Wu, L, Guo, X, Li, B, Schildkraut, JM, Im, HK, Chen, YA, Permuth, JB, Reid, BM, Teer, JK, Moysich, KB, Andrulis, IL, Anton-Culver, H, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Benitez, J, Bjorge, L, Brenton, J, Butzow, R, Caldes, T, Caligo, MA, Campbell, I, Chang-Claude, J, Claes, KBM, Couch, FJ, Cramer, DW, Daly, MB, DeFazio, A, Dennis, J, Diez, O, Domchek, SM, D rk, T, Easton, DF, Eccles, DM, Fasching, PA, Fortner, RET, Fountzilas, G, Friedman, E, Ganz, PA, Garber, J, Giles, GG, Godwin, AK, Goldgar, DE, Goodman, MT, Greene, MH, Gronwald, J, Hamann, U, Heitz, F, Hildebrandt, MAT, Høgdall, CK, Hollestelle, A, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, P, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Kwong, A, Le, ND, Leslie, G, Lesueur, F, Levine, DA, Mattiello, A, May, T, McGuffog, L, McNeish, IA, Merritt, MA, Modugno, F, Montagna, M, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olson, SH, Olsson, HK, Osorio, A, Park, SK, Parsons, MT, Peeters, PHM, Pejovic, T, Peterlongo, P, Phelan, CM, Pujana, MA, Ramus, SJ, Rennert, G, Risch, H, Rodriguez, GC, Rodríguez-Antona, C, Romieu, I, Rookus, MA, Rossing, MA, Rzepecka, IK, Sandler, DP, Schmutzler, RK, Setiawan, VW, Sharma, P, Sieh, W, Simard, J, Singer, CF, Song, H, Southey, MC, Spurdle, AB, Sutphen, R, Swerdlow, AJ, Teixeira, MR, Teo, SH, Thomassen, M, Tischkowitz, M, Toland, AE, Trichopoulou, A, Tung, N, Tworoger, SS, Van Rensburg, EJ, Vanderstichele, A, Vega, A, Edwards, DV, Webb, PM, Weitzel, JN, Wentzensen, N, White, E, Wolk, A, Wu, AH, Yannoukakos, D, Zorn, KK, Gayther, SA, Antoniou, AC, Berchuck, A, Goode, EL, Chenevix-Trench, G, Sellers, TA, Pharoah, PDP, Zheng, W & Long, J 2018, 'A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk', Cancer Research, vol. 78, no. 18, pp. 5419-5430. https://doi.org/10.1158/0008-5472.CAN-18-0951

TY - JOUR

T1 - A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk

AU - Lu, Yingchang

AU - Beeghly-Fadiel, Alicia

AU - Wu, Lang

AU - Guo, Xingyi

AU - Li, Bingshan

AU - Schildkraut, Joellen M.

AU - Im, Hae Kyung

AU - Chen, Yian A.

AU - Permuth, Jennifer B.

AU - Reid, Brett M.

AU - Teer, Jamie K.

AU - Moysich, Kirsten B.

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arun, Banu K.

AU - Bandera, Elisa V.

AU - Barkardottir, Rosa B.

AU - Barnes, Daniel R.

AU - Benitez, Javier

AU - Bjorge, Line

AU - Brenton, James

AU - Butzow, Ralf

AU - Caldes, Trinidad

AU - Caligo, Maria A.

AU - Campbell, Ian

AU - Chang-Claude, Jenny

AU - Claes, Kathleen B.M.

AU - Couch, Fergus J.

AU - Cramer, Daniel W.

AU - Daly, Mary B.

AU - DeFazio, Anna

AU - Dennis, Joe

AU - Diez, Orland

AU - Domchek, Susan M.

AU - D rk, Thilo

AU - Easton, Douglas F.

AU - Eccles, Diana M.

AU - Fasching, Peter A.

AU - Fortner, Ren e.T.

AU - Fountzilas, George

AU - Friedman, Eitan

AU - Ganz, Patricia A.

AU - Garber, Judy

AU - Giles, Graham G.

AU - Godwin, Andrew K.

AU - Goldgar, David E.

AU - Goodman, Marc T.

AU - Greene, Mark H.

AU - Gronwald, Jacek

AU - Hamann, Ute

AU - Heitz, Florian

AU - Hildebrandt, Michelle A.T.

AU - Høgdall, Claus K.

AU - Hollestelle, Antoinette

AU - Hulick, Peter J.

AU - Huntsman, David G.

AU - Imyanitov, Evgeny N.

AU - Isaacs, Claudine

AU - Jakubowska, Anna

AU - James, Paul

AU - Karlan, Beth Y.

AU - Kelemen, Linda E.

AU - Kiemeney, Lambertus A.

AU - Kjaer, Susanne K.

AU - Kwong, Ava

AU - Le, Nhu D.

AU - Leslie, Goska

AU - Lesueur, Fabienne

AU - Levine, Douglas A.

AU - Mattiello, Amalia

AU - May, Taymaa

AU - McGuffog, Lesley

AU - McNeish, Iain A.

AU - Merritt, Melissa A.

AU - Modugno, Francesmary

AU - Montagna, Marco

AU - Neuhausen, Susan L.

AU - Nevanlinna, Heli

AU - Nielsen, Finn C.

AU - Nikitina-Zake, Liene

AU - Nussbaum, Robert L.

AU - Offit, Kenneth

AU - Olah, Edith

AU - Olopade, Olufunmilayo I.

AU - Olson, Sara H.

AU - Olsson, H. kan

AU - Osorio, Ana

AU - Park, Sue K.

AU - Parsons, Michael T.

AU - Peeters, Petra H.M.

AU - Pejovic, Tanja

AU - Peterlongo, Paolo

AU - Phelan, Catherine M.

AU - Pujana, Miquel Angel

AU - Ramus, Susan J.

AU - Rennert, Gad

AU - Risch, Harvey

AU - Rodriguez, Gustavo C.

AU - Rodríguez-Antona, Cristina

AU - Romieu, Isabelle

AU - Rookus, Matti A.

AU - Rossing, Mary Anne

AU - Rzepecka, Iwona K.

AU - Sandler, Dale P.

AU - Schmutzler, Rita K.

AU - Setiawan, Veronica W.

AU - Sharma, Priyanka

AU - Sieh, Weiva

AU - Simard, Jacques

AU - Singer, Christian F.

AU - Song, Honglin

AU - Southey, Melissa C.

AU - Spurdle, Amanda B.

AU - Sutphen, Rebecca

AU - Swerdlow, Anthony J.

AU - Teixeira, Manuel R.

AU - Teo, Soo H.

AU - Thomassen, Mads

AU - Tischkowitz, Marc

AU - Toland, Amanda E.

AU - Trichopoulou, Antonia

AU - Tung, Nadine

AU - Tworoger, Shelley S.

AU - Van Rensburg, Elizabeth J.

AU - Vanderstichele, Adriaan

AU - Vega, Ana

AU - Edwards, Digna Velez

AU - Webb, Penelope M.

AU - Weitzel, Jeffrey N.

AU - Wentzensen, Nicolas

AU - White, Emily

AU - Wolk, Alicja

AU - Wu, Anna H.

AU - Yannoukakos, Drakoulis

AU - Zorn, Kristin K.

AU - Gayther, Simon A.

AU - Antoniou, Antonis C.

AU - Berchuck, Andrew

AU - Goode, Ellen L.

AU - Chenevix-Trench, Georgia

AU - Sellers, Thomas A.

AU - Pharoah, Paul D.P.

AU - Zheng, Wei

AU - Long, Jirong

N1 - Funding Information: The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium that was funded by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The OCAC OncoArray genotyping project was funded through grants from the NIH [U19-CA148112 (to T.A. Sellers), R01-CA149429 (to C.M. Phelan), and R01-CA058598 (to M.T. Goodman); Canadian Institutes of Health Research (MOP-86727 (to L.E. Kelemen)] and the Ovarian Cancer Research Fund (to A. Berchuck). The COGS project was funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). Funding for individual studies: AAS: NIH (RO1-CA142081); AOV: The Canadian Institutes for Health Research (MOP-86727); AUS: The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia (199600, 400413 and 400281), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia (Multi-State Applications 191, 211, and 182). The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation; BAV: ELAN Funds of the University of Erlangen-Nuremberg; BEL: National Kankerplan; BGS: Breast Cancer Now, Institute of Cancer Research; BVU: Vanderbilt CTSA grant from the National Institutes of Health (NIH)/ National Center for Advancing Translational Sciences (NCATS) (ULTR000445); CAM: National Institutes of Health Research Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre; CHA: Innovative Research Team in University (PCSIRT) in China (IRT1076); CNI: Instituto de Salud Carlos III (PI 12/01319); Ministerio de Economía y Competitividad (SAF2012); COE: Department of Defense (W81XWH-11-2-0131); CON: National Institutes of Health (R01-CA063678, R01-CA074850; R01-CA080742); DKE: Ovarian Cancer Research Fund and National Institutes of Health 1R01CA211574 (J.M. Schildkraut); DOV: National Institutes of Health R01-CA112523 and R01-CA87538; EMC: Dutch Cancer Society (EMC 2014-6699); EPC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santéet de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Funding Information: Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Ska°ne and V€asterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom); GER: German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ); GRC: This research has been co-financed by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Frame-work (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund; GRR: Roswell Park Cancer Institute Alliance Foundation, P30 CA016056; HAW: U.S. National Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001); HJO: Intramural funding; Rudolf-Bartling Foundation; HMO: Intramural funding; Rudolf-Bartling Foundation; HOC: Helsinki University Research Fund; HOP: Department of Defense (DAMD17-02-1-0669) and NCI (K07-CA080668, R01-CA95023, P50-CA159981 MO1-RR000056 R01-CA126841); HUO: Intramural funding; Rudolf-Bartling Foundation; JGO: JSPS KAKENHI grant; JPN: Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare; KRA: This study (Ko-EVE) was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 0920010); LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; LUN: ERC-2011-AdG 294576-risk factors cancer, Swedish Cancer Society, Swedish Research Council, Beta Kamprad Foundation; MAC: NIH (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Fraternal Order of Eagles; MAL: Funding for this study was provided by research grant R01-CA61107 from the National Cancer Institute, Bethesda, MD, research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project; MAS: Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; MAY: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MCC: Cancer Council Victoria, National Health and Medical Research Council of Australia (NHMRC) grants number 209057, 251533, 396414, and 504715; MDA: DOD Ovarian Cancer Research Program (W81XWH-07-0449); MEC: NIH (CA54281, CA164973, CA63464); MOF: Moffitt Cancer Center, Merck Pharmaceuticals, the state of Florida, Hillsborough County, and the city of Tampa; NCO: National Institutes of Health (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802; NHS: UM1 CA186107, P01 CA87969, R01 CA49449, R01-CA67262, UM1 CA176726; NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, P30-CA072720, and P30-CA008748) and the Cancer Institute of New Jersey; NOR: Helse Vest, The Norwegian Cancer Society, The Research Council of Norway; NTH: Radboud University Medical Centre; OPL: National Health and Medical Research Council (NHMRC) of Australia (APP1025142) and Brisbane Women's Club; ORE: OHSU Foundation; OVA: This work was supported by Canadian Institutes of Health Research grant (MOP-86727) and by NIH/NCI 1 R01CA160669-01A1; PLC: Intramural Research Program of the National Cancer Institute; POC: Pomeranian Medical University; POL: Intramural Research Program of the National Cancer Institute; PVD: Canadian Cancer Society and Cancer Research Society GRePEC Program; RBH: National Health and Medical Research Council of Australia; RMH: Cancer Research UK, Royal Marsden Hospital; RPC: National Institute of Health (P50 CA159981, R01CA126841); SEA: Cancer Research UK (C490/A10119 C490/ A10124); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; SIS: NIH, National Institute of Environmental Health Sciences, Z01 ES044005 and Z01-ES049033; SMC: The Swedish Research Council; SON: National Health Research and Development Program, Health Canada, grant 6613-1415-53; SRO: Cancer Research UK (C536/A13086, C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589); STA: NIH grants U01 CA71966 and U01 CA69417; SWE: Swedish Cancer foundation, WeCanCureCancer and a°rKampMotCancer foundation; SWH: NIH (NCI) grant R37-CA070867; TBO: National Institutes of Health (R01-CA106414-A2), American Cancer Society (CRTG-00-196-01-CCE), Department of Defense (DAMD17-98-1-8659), Celma Mastery Ovarian Cancer Foundation; TOR: NIH grants R01 CA063678 and R01 CA063682; UCI: NIH R01-CA058860 and the Lon V Smith Foundation grant LVS-39420; UHN: Princess Margaret Cancer Centre Foundation-Bridge for the Cure; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre; UKR: Cancer Research UK (C490/A6187), UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; USC: P01CA17054, P30CA14089, R01CA61132, N01PC67010, R03CA113148, R03CA115195, N01CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200); VAN: BC Cancer Foundation, VGH & UBC Hospital Foundation; VTL: NIH K05-CA154337; WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 & ID 628903. Cancer Institute NSW Grants 12/RIG/ 1-17 & 15/RIG/1-16; WOC: National Science Centren (N N301 5645 40). The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. We are grateful to the family and friends of Kathryn Sladek Smith for their generous support of the Ovarian Cancer Association Consortium through their donations to the Ovarian Cancer Research Fund. The OncoArray and COGS genotyping projects would not have been possible without the contributions of the following: Per Hall (COGS); Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Marjorie J. Riggan (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Jonathan P. Tyrer, Siddhartha Kar, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. We pay special tribute to the contribution of Professor Brian Henderson to the GAME-ON consortium and to Olga M. Sinilnikova for her contribution to CIMBA and for her part in the initiation and coordination of GEMO until she sadly passed away on the 30th June 2014. We thank the study participants, doctors, nurses, clinical and scientific collaborators, health care providers and health information sources who have contributed to the many studies contributing to this manuscript. Funding Information: Acknowledgements for individual studies: AOV: We thank Jennifer Koziak, Mie Konno, Michelle Darago, Faye Chambers and the Tom Baker Cancer Centre Translational Laboratories; AUS: The AOCS also acknowledges the cooperation of the participating institutions in Australia and acknowledges the contribution of the study nurses, research assistants and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www. aocstudy.org.We would like tothankallofthewomen who participated inthese research programs; BEL: We would like to thank Gilian Peuteman, Thomas Van Brussel, Annick Van den Broeck and Joke De Roover for technical assistance; BGS: The BGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. We thank the Study staff, study participants, doctors, nurses, health care providers and health information sources who have contributed to the study; BVU: The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH; CAM: This work was supported by Cancer Research UK; the University of Cambridge; National Institute for Health Research Cambridge Biomedical Research Centre; CHA: Innovative Research Team in University (PCSIRT) in China (IRT1076); CHN: To thank all members of Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital and Department of Molecular Biology, Hebei Medical University, Fourth Hospital; COE: Gynecologic Cancer Center of Excellence (W81XWH-11-2-0131); CON: The cooperation of the 32 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. This study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in this study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data; DKE: OCRF; EPC: To thank Funding Information: all members and investigators of the Rotterdam Ovarian Cancer Study. Dutch Cancer Society (EMC 2014-6699); GER: The German Ovarian Cancer Study (GER) thank Ursula Eilber for competent technical assistance; HOC: The study was supported by the Helsinki University Research Fund; JGO: JSPS KAKENHI grant; KRA: This study (Ko-EVE) was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 0920010); LUN: ERC -2011-AdG, Swedish Cancer Society, Swedish Research Council; MAS: We would like to thank Famida Zulkifli and Ms Moey for assistance in patient recruitment, data collection and sample preparation. The Malaysian Ovarian Cancer Genetic Study is funded by research grants from the Malaysian Ministry of Higher Education (UM.C/HIR/MOHE/06) and charitable funding from Cancer Research Initiatives Foundation; MCC: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database; MOF: the Total Cancer Care Protocol and the Collaborative Data Services and Tissue Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292), Merck Pharmaceuticals and the state of Florida; NHS: The NHS/NHSII studies thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY; NJO: L. Paddock, M. King, U. Chandran, A. Samoila, and Y. Bensman; OPL: Members of the OPAL Study Group (http://opalstudy.qimrberghofer.edu.au/); RPC: National Institute of Health (P50 CA159981, R01CA126841); SEA: SEARCH Publisher Copyright: © 2018 American Association for Cancer Research.

PY - 2018/9/15

Y1 - 2018/9/15

N2 - Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 10 6 , we identified 35 genes, including FZD4 at 11q14.2 (Z ¼ 5.08, P ¼ 3.83 10 7 , the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 10 3 ). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.

AB - Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 10 6 , we identified 35 genes, including FZD4 at 11q14.2 (Z ¼ 5.08, P ¼ 3.83 10 7 , the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 10 3 ). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.

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U2 - 10.1158/0008-5472.CAN-18-0951

DO - 10.1158/0008-5472.CAN-18-0951

M3 - Article

C2 - 30054336

AN - SCOPUS:85053297183

SN - 0008-5472

VL - 78

SP - 5419

EP - 5430

JO - Cancer Research

JF - Cancer Research

IS - 18

ER -

A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk

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