A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24

Ellen L. Goode; Georgia Chenevix-Trench; Honglin Song; Susan J. Ramus; Maria Notaridou; Kate Lawrenson; Martin Widschwendter; Robert A. Vierkant; Melissa C. Larson; Susanne K. Kjaer; Michael J. Birrer; Andrew Berchuck; Joellen Schildkraut; Ian Tomlinson; Lambertus A. Kiemeney; Linda S. Cook; Jacek Gronwald; Montserrat Garcia-Closas; Martin E. Gore; Ian Campbell; Alice S. Whittemore; Rebecca Sutphen; Catherine Phelan; Hoda Anton-Culver; Celeste Leigh Pearce; Diether Lambrechts; Mary Anne Rossing; Jenny Chang-Claude; Kirsten B. Moysich; Marc T. Goodman; Thilo Dörk; Heli Nevanlinna; Roberta B. Ness; Thorunn Rafnar; Claus Hogdall; Estrid Hogdall; Brooke L. Fridley; Julie M. Cunningham; Weiva Sieh; Valerie McGuire; Andrew K. Godwin; Daniel W. Cramer; Dena Hernandez; Douglas Levine; Karen Lu; Edwin S. Iversen; Rachel T. Palmieri; Richard Houlston; Anne M. Van Altena; Katja K.H. Aben; Leon F.A.G. Massuger; Angela Brooks-Wilson; Linda E. Kelemen; Nhu D. Le; Anna Jakubowska; Jan Lubinski; Krzysztof Medrek; Anne Stafford; Douglas F. Easton; Jonathan Tyrer; Kelly L. Bolton; Patricia Harrington; Diana Eccles; Ann Chen; Ashley N. Molina; Barbara N. Davila; Hector Arango; Ya Yu Tsai; Zhihua Chen; Harvey A. Risch; John McLaughlin; Steven A. Narod; Argyrios Ziogas; Wendy Brewster; Aleksandra Gentry-Maharaj; Usha Menon; Anna H. Wu; Daniel O. Stram; Malcolm C. Pike; Jonathan Beesley; Penelope M. Webb; Xiaoqing Chen; Arif B. Ekici; Falk C. Thiel; Matthias W. Beckmann; Hannah Yang; Nicolas Wentzensen; Jolanta Lissowska; Peter A. Fasching; Evelyn Despierre; Frederic Amant; Ignace Vergote; Jennifer Doherty; Rebecca Hein; Shan Wang-Gohrke; Galina Lurie; Michael E. Carney; Pamela J. Thompson; Ingo Runnebaum; Peter Hillemanns; Matthias Dürst; Natalia Antonenkova; Natalia Bogdanova; Arto Leminen; Ralf Butzow; Tuomas Heikkinen; Kari Stefansson; Patrick Sulem; Sören Besenbacher; Thomas A. Sellers; Simon A. Gayther; Paul D.P. Pharoah

doi:10.1038/ng.668

A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24

Ellen L. Goode, Georgia Chenevix-Trench, Honglin Song, Susan J. Ramus, Maria Notaridou, Kate Lawrenson, Martin Widschwendter, Robert A. Vierkant, Melissa C. Larson, Susanne K. Kjaer, Michael J. Birrer, Andrew Berchuck, Joellen Schildkraut, Ian Tomlinson, Lambertus A. Kiemeney, Linda S. Cook, Jacek Gronwald, Montserrat Garcia-Closas, Martin E. Gore, Ian CampbellAlice S. Whittemore, Rebecca Sutphen, Catherine Phelan, Hoda Anton-Culver, Celeste Leigh Pearce, Diether Lambrechts, Mary Anne Rossing, Jenny Chang-Claude, Kirsten B. Moysich, Marc T. Goodman, Thilo Dörk, Heli Nevanlinna, Roberta B. Ness, Thorunn Rafnar, Claus Hogdall, Estrid Hogdall, Brooke L. Fridley, Julie M. Cunningham, Weiva Sieh, Valerie McGuire, Andrew K. Godwin, Daniel W. Cramer, Dena Hernandez, Douglas Levine, Karen Lu, Edwin S. Iversen, Rachel T. Palmieri, Richard Houlston, Anne M. Van Altena, Katja K.H. Aben, Leon F.A.G. Massuger, Angela Brooks-Wilson, Linda E. Kelemen, Nhu D. Le, Anna Jakubowska, Jan Lubinski, Krzysztof Medrek, Anne Stafford, Douglas F. Easton, Jonathan Tyrer, Kelly L. Bolton, Patricia Harrington, Diana Eccles, Ann Chen, Ashley N. Molina, Barbara N. Davila, Hector Arango, Ya Yu Tsai, Zhihua Chen, Harvey A. Risch, John McLaughlin, Steven A. Narod, Argyrios Ziogas, Wendy Brewster, Aleksandra Gentry-Maharaj, Usha Menon, Anna H. Wu, Daniel O. Stram, Malcolm C. Pike, Jonathan Beesley, Penelope M. Webb, Xiaoqing Chen, Arif B. Ekici, Falk C. Thiel, Matthias W. Beckmann, Hannah Yang, Nicolas Wentzensen, Jolanta Lissowska, Peter A. Fasching, Evelyn Despierre, Frederic Amant, Ignace Vergote, Jennifer Doherty, Rebecca Hein, Shan Wang-Gohrke, Galina Lurie, Michael E. Carney, Pamela J. Thompson, Ingo Runnebaum, Peter Hillemanns, Matthias Dürst, Natalia Antonenkova, Natalia Bogdanova, Arto Leminen, Ralf Butzow, Tuomas Heikkinen, Kari Stefansson, Patrick Sulem, Sören Besenbacher, Thomas A. Sellers, Simon A. Gayther, Paul D.P. Pharoah

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

302 Scopus citations

Abstract

Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P 10 -4) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P -5 × 10 -8 (8q24, P = 8.0 × 10 -15 and 2q31, P = 3.8 × 10 -14) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10 -8 and 17q21, P = 1.4 × 10 -7). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.

Original language	English
Pages (from-to)	874-879
Number of pages	6
Journal	Nature Genetics
Volume	42
Issue number	10
DOIs	https://doi.org/10.1038/ng.668
State	Published - Oct 2010
Externally published	Yes

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10.1038/ng.668

Cite this

Goode, E. L., Chenevix-Trench, G., Song, H., Ramus, S. J., Notaridou, M., Lawrenson, K., Widschwendter, M., Vierkant, R. A., Larson, M. C., Kjaer, S. K., Birrer, M. J., Berchuck, A., Schildkraut, J., Tomlinson, I., Kiemeney, L. A., Cook, L. S., Gronwald, J., Garcia-Closas, M., Gore, M. E., ... Pharoah, P. D. P. (2010). A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nature Genetics, 42(10), 874-879. https://doi.org/10.1038/ng.668

@article{8973c094522c4c1d82287430b47b2364,

title = "A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24",

abstract = "Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P 10 -4) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P -5 × 10 -8 (8q24, P = 8.0 × 10 -15 and 2q31, P = 3.8 × 10 -14) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10 -8 and 17q21, P = 1.4 × 10 -7). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.",

author = "Goode, {Ellen L.} and Georgia Chenevix-Trench and Honglin Song and Ramus, {Susan J.} and Maria Notaridou and Kate Lawrenson and Martin Widschwendter and Vierkant, {Robert A.} and Larson, {Melissa C.} and Kjaer, {Susanne K.} and Birrer, {Michael J.} and Andrew Berchuck and Joellen Schildkraut and Ian Tomlinson and Kiemeney, {Lambertus A.} and Cook, {Linda S.} and Jacek Gronwald and Montserrat Garcia-Closas and Gore, {Martin E.} and Ian Campbell and Whittemore, {Alice S.} and Rebecca Sutphen and Catherine Phelan and Hoda Anton-Culver and Pearce, {Celeste Leigh} and Diether Lambrechts and Rossing, {Mary Anne} and Jenny Chang-Claude and Moysich, {Kirsten B.} and Goodman, {Marc T.} and Thilo D{\"o}rk and Heli Nevanlinna and Ness, {Roberta B.} and Thorunn Rafnar and Claus Hogdall and Estrid Hogdall and Fridley, {Brooke L.} and Cunningham, {Julie M.} and Weiva Sieh and Valerie McGuire and Godwin, {Andrew K.} and Cramer, {Daniel W.} and Dena Hernandez and Douglas Levine and Karen Lu and Iversen, {Edwin S.} and Palmieri, {Rachel T.} and Richard Houlston and {Van Altena}, {Anne M.} and Aben, {Katja K.H.} and Massuger, {Leon F.A.G.} and Angela Brooks-Wilson and Kelemen, {Linda E.} and Le, {Nhu D.} and Anna Jakubowska and Jan Lubinski and Krzysztof Medrek and Anne Stafford and Easton, {Douglas F.} and Jonathan Tyrer and Bolton, {Kelly L.} and Patricia Harrington and Diana Eccles and Ann Chen and Molina, {Ashley N.} and Davila, {Barbara N.} and Hector Arango and Tsai, {Ya Yu} and Zhihua Chen and Risch, {Harvey A.} and John McLaughlin and Narod, {Steven A.} and Argyrios Ziogas and Wendy Brewster and Aleksandra Gentry-Maharaj and Usha Menon and Wu, {Anna H.} and Stram, {Daniel O.} and Pike, {Malcolm C.} and Jonathan Beesley and Webb, {Penelope M.} and Xiaoqing Chen and Ekici, {Arif B.} and Thiel, {Falk C.} and Beckmann, {Matthias W.} and Hannah Yang and Nicolas Wentzensen and Jolanta Lissowska and Fasching, {Peter A.} and Evelyn Despierre and Frederic Amant and Ignace Vergote and Jennifer Doherty and Rebecca Hein and Shan Wang-Gohrke and Galina Lurie and Carney, {Michael E.} and Thompson, {Pamela J.} and Ingo Runnebaum and Peter Hillemanns and Matthias D{\"u}rst and Natalia Antonenkova and Natalia Bogdanova and Arto Leminen and Ralf Butzow and Tuomas Heikkinen and Kari Stefansson and Patrick Sulem and S{\"o}ren Besenbacher and Sellers, {Thomas A.} and Gayther, {Simon A.} and Pharoah, {Paul D.P.}",

note = "Funding Information: This study made use of data generated by the Wellcome Trust Case Control consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113. 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. The MAL study is supported by grants from Mermaid 1, the Danish Cancer Society and the National Cancer Institute, Bethesda, Maryland, USA (R01-CA-61107). The MAY study and the phase 3 and combined analyses were supported by the US National Institutes of Health, National Cancer Institute grants R01-CA-122443 and funding from the Mayo Foundation. The PBCS was funded by Intramural Research Funds of the US National Cancer Institute, Department of Health and Human Services. The Fox Chase Cancer Center ovarian cancer study, part of the National Cancer Institute collaboration, is supported by an Ovarian Cancer Specialized Program of Research Excellence (SPORE) (P50 CA083638). The NCO study is supported by the US National Institutes of Health, National Cancer Institute grant R01-CA-76016. The SEA study is funded by a programme grant from Cancer Research UK. We thank the SEARCH team and the Eastern Cancer Registration and Information Centre for subject recruitment. The TBO study was supported by the US National Institutes of Health (R01-CA106414); the American Cancer Society (CRTG-00-196-01-CCE); and the Advanced Cancer Detection Center Grant, Department of Defense (DAMD17-98-1-8659). The TOR study was supported by grants from the Canadian Institutes for Health Research, the National Cancer Institute of Canada with funds provided by the Canadian Cancer Society and the US National Institutes of Health (R01-CA-63682 and R01-CA-63678). Additional support for the TOR, NCO, MAY, TBO and NCI studies was provided by the University of California, Irvine grant R01-CA-114343. The UCI study is supported by the US National Institutes of Health, National Cancer Institute grants CA-58860, CA-92044 and the Lon V Smith Foundation grant LVS-39420. The UKO study is supported by funding from Cancer Research UK, the Eve Appeal and the OAK Foundation. Some of this work was undertaken at University College London Hospital/University College London, who received a proportion of funding from the Department of Health{\textquoteright}s National Institutes for Health Research Biomedical Research Centre funding scheme. We particularly thank I. Jacobs, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study. The AUS study is supported by the National Health and Medical Research Council of Australia (199600), US Army Medical Research and Materiel Command under DAMD17-01-1-0729 (award no. W81XWH-06-1-0220) and the Cancer Council Tasmania and Cancer Foundation of Western Australia. G.C.-M.T. and P.M.W. are Research Fellows of the National Health and Medical Research Council. The Australian Ovarian Cancer Study (AOCS) Management Group (D. Bowtell, A. deFazio, G.C.-T., D.G., A.K.G. and P.M.W.) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/). The Australian Cancer Study (ACS) Management Group comprises P.D.P.P., P.M.W., A. Green, N. Hayward and D. Whiteman. The BAV study is supported by the ELAN Foundation and Erlangen University Hospital. The BEL study is supported by the National Cancer Plan-Action 29 for the support of Translational Research. The DOV study (Seattle Diseases of the Ovary) was supported by the US National Institutes of Health grants R01-CA-112523 and R01-CA-87538. The GER study was supported by the German Federal Ministry of Education and Research of Germany, the Programme of Clinical Biomedical Research (01 GB 9401), and the genotyping was supported in part by the state of Baden-W{\"u}rttemberg through the Medical Faculty, University of Ulm (P.685). Data management was supported by the German Cancer Research Center. The HAW study was supported by the US Public Health Service grant R01-CA-58598 and contracts N01-CN-55424, N01-PC-67001 and N01-PC-35137 from the National Cancer Institute, US National Institutes of Health, Department of Health and Human Services. Funding for the USC study was received from the California Cancer Research Program grants 00-01389V-20170 and 2110200, US Public Health Service grants CA14089, CA17054, CA61132, CA63464, N01-PC-67010 and R03-CA113148 and the California Department of Health Services sub-contract 050-E8709 as part of its statewide cancer reporting program (University of Southern California). The HJO study gratefully acknowledges the contribution of F. Kramer and W. Zheng to the recruitment of subjects at Hannover Medical School. The HMO study gratefully acknowledges the help of L. Gacucova in sample preparation. Funding Information: The HOC study was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland and the Finnish Cancer Society.",

year = "2010",

month = oct,

doi = "10.1038/ng.668",

language = "English",

volume = "42",

pages = "874--879",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

Goode, EL, Chenevix-Trench, G, Song, H, Ramus, SJ, Notaridou, M, Lawrenson, K, Widschwendter, M, Vierkant, RA, Larson, MC, Kjaer, SK, Birrer, MJ, Berchuck, A, Schildkraut, J, Tomlinson, I, Kiemeney, LA, Cook, LS, Gronwald, J, Garcia-Closas, M, Gore, ME, Campbell, I, Whittemore, AS, Sutphen, R, Phelan, C, Anton-Culver, H, Pearce, CL, Lambrechts, D, Rossing, MA, Chang-Claude, J, Moysich, KB, Goodman, MT, Dörk, T, Nevanlinna, H, Ness, RB, Rafnar, T, Hogdall, C, Hogdall, E, Fridley, BL, Cunningham, JM, Sieh, W, McGuire, V, Godwin, AK, Cramer, DW, Hernandez, D, Levine, D, Lu, K, Iversen, ES, Palmieri, RT, Houlston, R, Van Altena, AM, Aben, KKH, Massuger, LFAG, Brooks-Wilson, A, Kelemen, LE, Le, ND, Jakubowska, A, Lubinski, J, Medrek, K, Stafford, A, Easton, DF, Tyrer, J, Bolton, KL, Harrington, P, Eccles, D, Chen, A, Molina, AN, Davila, BN, Arango, H, Tsai, YY, Chen, Z, Risch, HA, McLaughlin, J, Narod, SA, Ziogas, A, Brewster, W, Gentry-Maharaj, A, Menon, U, Wu, AH, Stram, DO, Pike, MC, Beesley, J, Webb, PM, Chen, X, Ekici, AB, Thiel, FC, Beckmann, MW, Yang, H, Wentzensen, N, Lissowska, J, Fasching, PA, Despierre, E, Amant, F, Vergote, I, Doherty, J, Hein, R, Wang-Gohrke, S, Lurie, G, Carney, ME, Thompson, PJ, Runnebaum, I, Hillemanns, P, Dürst, M, Antonenkova, N, Bogdanova, N, Leminen, A, Butzow, R, Heikkinen, T, Stefansson, K, Sulem, P, Besenbacher, S, Sellers, TA, Gayther, SA & Pharoah, PDP 2010, 'A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24', Nature Genetics, vol. 42, no. 10, pp. 874-879. https://doi.org/10.1038/ng.668

TY - JOUR

T1 - A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24

AU - Goode, Ellen L.

AU - Chenevix-Trench, Georgia

AU - Song, Honglin

AU - Ramus, Susan J.

AU - Notaridou, Maria

AU - Lawrenson, Kate

AU - Widschwendter, Martin

AU - Vierkant, Robert A.

AU - Larson, Melissa C.

AU - Kjaer, Susanne K.

AU - Birrer, Michael J.

AU - Berchuck, Andrew

AU - Schildkraut, Joellen

AU - Tomlinson, Ian

AU - Kiemeney, Lambertus A.

AU - Cook, Linda S.

AU - Gronwald, Jacek

AU - Garcia-Closas, Montserrat

AU - Gore, Martin E.

AU - Campbell, Ian

AU - Whittemore, Alice S.

AU - Sutphen, Rebecca

AU - Phelan, Catherine

AU - Anton-Culver, Hoda

AU - Pearce, Celeste Leigh

AU - Lambrechts, Diether

AU - Rossing, Mary Anne

AU - Chang-Claude, Jenny

AU - Moysich, Kirsten B.

AU - Goodman, Marc T.

AU - Dörk, Thilo

AU - Nevanlinna, Heli

AU - Ness, Roberta B.

AU - Rafnar, Thorunn

AU - Hogdall, Claus

AU - Hogdall, Estrid

AU - Fridley, Brooke L.

AU - Cunningham, Julie M.

AU - Sieh, Weiva

AU - McGuire, Valerie

AU - Godwin, Andrew K.

AU - Cramer, Daniel W.

AU - Hernandez, Dena

AU - Levine, Douglas

AU - Lu, Karen

AU - Iversen, Edwin S.

AU - Palmieri, Rachel T.

AU - Houlston, Richard

AU - Van Altena, Anne M.

AU - Aben, Katja K.H.

AU - Massuger, Leon F.A.G.

AU - Brooks-Wilson, Angela

AU - Kelemen, Linda E.

AU - Le, Nhu D.

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Medrek, Krzysztof

AU - Stafford, Anne

AU - Easton, Douglas F.

AU - Tyrer, Jonathan

AU - Bolton, Kelly L.

AU - Harrington, Patricia

AU - Eccles, Diana

AU - Chen, Ann

AU - Molina, Ashley N.

AU - Davila, Barbara N.

AU - Arango, Hector

AU - Tsai, Ya Yu

AU - Chen, Zhihua

AU - Risch, Harvey A.

AU - McLaughlin, John

AU - Narod, Steven A.

AU - Ziogas, Argyrios

AU - Brewster, Wendy

AU - Gentry-Maharaj, Aleksandra

AU - Menon, Usha

AU - Wu, Anna H.

AU - Stram, Daniel O.

AU - Pike, Malcolm C.

AU - Beesley, Jonathan

AU - Webb, Penelope M.

AU - Chen, Xiaoqing

AU - Ekici, Arif B.

AU - Thiel, Falk C.

AU - Beckmann, Matthias W.

AU - Yang, Hannah

AU - Wentzensen, Nicolas

AU - Lissowska, Jolanta

AU - Fasching, Peter A.

AU - Despierre, Evelyn

AU - Amant, Frederic

AU - Vergote, Ignace

AU - Doherty, Jennifer

AU - Hein, Rebecca

AU - Wang-Gohrke, Shan

AU - Lurie, Galina

AU - Carney, Michael E.

AU - Thompson, Pamela J.

AU - Runnebaum, Ingo

AU - Hillemanns, Peter

AU - Dürst, Matthias

AU - Antonenkova, Natalia

AU - Bogdanova, Natalia

AU - Leminen, Arto

AU - Butzow, Ralf

AU - Heikkinen, Tuomas

AU - Stefansson, Kari

AU - Sulem, Patrick

AU - Besenbacher, Sören

AU - Sellers, Thomas A.

AU - Gayther, Simon A.

AU - Pharoah, Paul D.P.

N1 - Funding Information: This study made use of data generated by the Wellcome Trust Case Control consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113. 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. The MAL study is supported by grants from Mermaid 1, the Danish Cancer Society and the National Cancer Institute, Bethesda, Maryland, USA (R01-CA-61107). The MAY study and the phase 3 and combined analyses were supported by the US National Institutes of Health, National Cancer Institute grants R01-CA-122443 and funding from the Mayo Foundation. The PBCS was funded by Intramural Research Funds of the US National Cancer Institute, Department of Health and Human Services. The Fox Chase Cancer Center ovarian cancer study, part of the National Cancer Institute collaboration, is supported by an Ovarian Cancer Specialized Program of Research Excellence (SPORE) (P50 CA083638). The NCO study is supported by the US National Institutes of Health, National Cancer Institute grant R01-CA-76016. The SEA study is funded by a programme grant from Cancer Research UK. We thank the SEARCH team and the Eastern Cancer Registration and Information Centre for subject recruitment. The TBO study was supported by the US National Institutes of Health (R01-CA106414); the American Cancer Society (CRTG-00-196-01-CCE); and the Advanced Cancer Detection Center Grant, Department of Defense (DAMD17-98-1-8659). The TOR study was supported by grants from the Canadian Institutes for Health Research, the National Cancer Institute of Canada with funds provided by the Canadian Cancer Society and the US National Institutes of Health (R01-CA-63682 and R01-CA-63678). Additional support for the TOR, NCO, MAY, TBO and NCI studies was provided by the University of California, Irvine grant R01-CA-114343. The UCI study is supported by the US National Institutes of Health, National Cancer Institute grants CA-58860, CA-92044 and the Lon V Smith Foundation grant LVS-39420. The UKO study is supported by funding from Cancer Research UK, the Eve Appeal and the OAK Foundation. Some of this work was undertaken at University College London Hospital/University College London, who received a proportion of funding from the Department of Health’s National Institutes for Health Research Biomedical Research Centre funding scheme. We particularly thank I. Jacobs, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study. The AUS study is supported by the National Health and Medical Research Council of Australia (199600), US Army Medical Research and Materiel Command under DAMD17-01-1-0729 (award no. W81XWH-06-1-0220) and the Cancer Council Tasmania and Cancer Foundation of Western Australia. G.C.-M.T. and P.M.W. are Research Fellows of the National Health and Medical Research Council. The Australian Ovarian Cancer Study (AOCS) Management Group (D. Bowtell, A. deFazio, G.C.-T., D.G., A.K.G. and P.M.W.) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/). The Australian Cancer Study (ACS) Management Group comprises P.D.P.P., P.M.W., A. Green, N. Hayward and D. Whiteman. The BAV study is supported by the ELAN Foundation and Erlangen University Hospital. The BEL study is supported by the National Cancer Plan-Action 29 for the support of Translational Research. The DOV study (Seattle Diseases of the Ovary) was supported by the US National Institutes of Health grants R01-CA-112523 and R01-CA-87538. The GER study was supported by the German Federal Ministry of Education and Research of Germany, the Programme of Clinical Biomedical Research (01 GB 9401), and the genotyping was supported in part by the state of Baden-Württemberg through the Medical Faculty, University of Ulm (P.685). Data management was supported by the German Cancer Research Center. The HAW study was supported by the US Public Health Service grant R01-CA-58598 and contracts N01-CN-55424, N01-PC-67001 and N01-PC-35137 from the National Cancer Institute, US National Institutes of Health, Department of Health and Human Services. Funding for the USC study was received from the California Cancer Research Program grants 00-01389V-20170 and 2110200, US Public Health Service grants CA14089, CA17054, CA61132, CA63464, N01-PC-67010 and R03-CA113148 and the California Department of Health Services sub-contract 050-E8709 as part of its statewide cancer reporting program (University of Southern California). The HJO study gratefully acknowledges the contribution of F. Kramer and W. Zheng to the recruitment of subjects at Hannover Medical School. The HMO study gratefully acknowledges the help of L. Gacucova in sample preparation. Funding Information: The HOC study was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland and the Finnish Cancer Society.

PY - 2010/10

Y1 - 2010/10

N2 - Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P 10 -4) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P -5 × 10 -8 (8q24, P = 8.0 × 10 -15 and 2q31, P = 3.8 × 10 -14) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10 -8 and 17q21, P = 1.4 × 10 -7). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.

AB - Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P 10 -4) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P -5 × 10 -8 (8q24, P = 8.0 × 10 -15 and 2q31, P = 3.8 × 10 -14) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10 -8 and 17q21, P = 1.4 × 10 -7). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.

UR - http://www.scopus.com/inward/record.url?scp=77957571905&partnerID=8YFLogxK

U2 - 10.1038/ng.668

DO - 10.1038/ng.668

M3 - Article

C2 - 20852632

AN - SCOPUS:77957571905

SN - 1061-4036

VL - 42

SP - 874

EP - 879

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24

Abstract

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