Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus

Melissa A. Buckley; Nicholas T. Woods; Jonathan P. Tyrer; Gustavo Mendoza-Fandiño; Kate Lawrenson; Dennis J. Hazelett; Hamed S. Najafabadi; Anxhela Gjyshi; Renato S. Carvalho; Paulo C. Lyra; Simon G. Coetzee; Howard C. Shen; Ally W. Yang; Madalene A. Earp; Sean J. Yoder; Harvey Risch; Georgia Chenevix-Trench; Susan J. Ramus; Catherine M. Phelan; Gerhard A. Coetzee; Houtan Noushmehr; Timothy R. Hughes; Thomas A. Sellers; Ellen L. Goode; Paul D. Pharoah; Simon A. Gayther; Alvaro N.A. Monteiro; Y. Ann Chen; Brooke L. Fridley; Katja K.H. Aben; Lambertus A. Kiemeney; Hoda Anton-Culver; Argyrios Ziogas; Fiona Bruinsma; Roger L. Milne; Elisa V. Bandera; Graham G. Giles; Yukie T. Bean; Tanja Pejovic; Matthias W. Beckmann; Alexander Hein; Line Bjorge; Peter A. Fasching; Liv C.V. Thomsen; Reidun K. Kopperud; Katharina Bischof; Natalia Bogdanova; Thilo Dörk; Peter Hillemanns; Louise A. Brinton; Nicolas Wentzensen; Hannah Yang; Angela Brooks-Wilson; Clareann H. Bunker; Ralf Butzow; Heli Nevanlinna; Liisa M. Pelttari; Ian G. Campbell; Melissa C. Southey; Francesmary Modugno; Karen Carty; Rosalind Glasspool; Ian McNeish; James Paul; Nadeem Siddiqui; Jenny Chang-Claude; Anja Rudolph; Linda S. Cook; Daniel W. Cramer; Kathryn L. Terry; Julie M. Cunningham; Cezary Cybulski; Jacek Gronwald; Anna Jakubowska; Jan Lubinski; Agnieszka Dansonka-Mieszkowska; Jolanta Kupryjanczyk; Iwona K. Rzepecka; Andreas Du Bois; Philipp Harter; Ed Dicks; Honglin Song; Jennifer A. Doherty; Mary Anne Rossing; Matthias Dürst; Douglas F. Easton; Diana M. Eccles; Robert P. Edwards; Arif B. Ekici; Yu Tang Gao; Aleksandra Gentry-Maharaj; Marc T. Goodman; Pamela J. Thompson; Hanis N. Hasmad; Soo Hwang Teo; Michelle A.T. Hildebrandt; Xifeng Wu; Estrid Hogdall; Allan Jensen; Susanne K. Kjaer; Edwin S. Iversen; Beth Y. Karlan; Jenny Lester; Sandra Orsulic; Christine S. Walsh; Joseph L. Kelley; Diether Lambrechts; Sandrina Lambrechts; Ignace Vergote; Alice W. Lee; Douglas A. Levine; Dong Liang; Jolanta Lissowska; Karen Lu; Lene Lundvall; Leon F.A.G. Massuger; Anne M. Van Altena; Keitaro Matsuo; Valerie McGuire; John R. McLaughlin; Usha Menon; Kirsten B. Moysich; Roberta B. Ness; Kunle Odunsi; Sara H. Olson; Irene Orlow; Malcolm C. Pike; Celeste L. Pearce; Anna H. Wu; Jennifer B. Permuth; Ya Yu Tsai; Shelley S. Tworoger; Elizabeth M. Poole; Barry Rosen; Xiao Ou Shu; Yurii B. Shvetsov; Lynne R. Wilkens; Weiva Sieh; Beata Spiewankiewicz; Lara Sucheston-Campbell; Lotte Thomsen; Shan Wang-Gohrke; Alice S. Whittemore; Yin Ling Woo; Wei Zheng; Andrew Berchuck; Joellen M. Schildkraut; Linda E. Kelemen; Matthew L. Freedman

doi:10.1158/0008-5472.CAN-17-3864

Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus

Melissa A. Buckley, Nicholas T. Woods, Jonathan P. Tyrer, Gustavo Mendoza-Fandiño, Kate Lawrenson, Dennis J. Hazelett, Hamed S. Najafabadi, Anxhela Gjyshi, Renato S. Carvalho, Paulo C. Lyra, Simon G. Coetzee, Howard C. Shen, Ally W. Yang, Madalene A. Earp, Sean J. Yoder, Harvey Risch, Georgia Chenevix-Trench, Susan J. Ramus, Catherine M. Phelan, Gerhard A. CoetzeeHoutan Noushmehr, Timothy R. Hughes, Thomas A. Sellers, Ellen L. Goode, Paul D. Pharoah, Simon A. Gayther, Alvaro N.A. Monteiro, Y. Ann Chen, Brooke L. Fridley, Katja K.H. Aben, Lambertus A. Kiemeney, Hoda Anton-Culver, Argyrios Ziogas, Fiona Bruinsma, Roger L. Milne, Elisa V. Bandera, Graham G. Giles, Yukie T. Bean, Tanja Pejovic, Matthias W. Beckmann, Alexander Hein, Line Bjorge, Peter A. Fasching, Liv C.V. Thomsen, Reidun K. Kopperud, Katharina Bischof, Natalia Bogdanova, Thilo Dörk, Peter Hillemanns, Louise A. Brinton, Nicolas Wentzensen, Hannah Yang, Angela Brooks-Wilson, Clareann H. Bunker, Ralf Butzow, Heli Nevanlinna, Liisa M. Pelttari, Ian G. Campbell, Melissa C. Southey, Francesmary Modugno, Karen Carty, Rosalind Glasspool, Ian McNeish, James Paul, Nadeem Siddiqui, Jenny Chang-Claude, Anja Rudolph, Linda S. Cook, Daniel W. Cramer, Kathryn L. Terry, Julie M. Cunningham, Cezary Cybulski, Jacek Gronwald, Anna Jakubowska, Jan Lubinski, Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk, Iwona K. Rzepecka, Andreas Du Bois, Philipp Harter, Ed Dicks, Honglin Song, Jennifer A. Doherty, Mary Anne Rossing, Matthias Dürst, Douglas F. Easton, Diana M. Eccles, Robert P. Edwards, Arif B. Ekici, Yu Tang Gao, Aleksandra Gentry-Maharaj, Marc T. Goodman, Pamela J. Thompson, Hanis N. Hasmad, Soo Hwang Teo, Michelle A.T. Hildebrandt, Xifeng Wu, Estrid Hogdall, Allan Jensen, Susanne K. Kjaer, Edwin S. Iversen, Beth Y. Karlan, Jenny Lester, Sandra Orsulic, Christine S. Walsh, Joseph L. Kelley, Diether Lambrechts, Sandrina Lambrechts, Ignace Vergote, Alice W. Lee, Douglas A. Levine, Dong Liang, Jolanta Lissowska, Karen Lu, Lene Lundvall, Leon F.A.G. Massuger, Anne M. Van Altena, Keitaro Matsuo, Valerie McGuire, John R. McLaughlin, Usha Menon, Kirsten B. Moysich, Roberta B. Ness, Kunle Odunsi, Sara H. Olson, Irene Orlow, Malcolm C. Pike, Celeste L. Pearce, Anna H. Wu, Jennifer B. Permuth, Ya Yu Tsai, Shelley S. Tworoger, Elizabeth M. Poole, Barry Rosen, Xiao Ou Shu, Yurii B. Shvetsov, Lynne R. Wilkens, Weiva Sieh, Beata Spiewankiewicz, Lara Sucheston-Campbell, Lotte Thomsen, Shan Wang-Gohrke, Alice S. Whittemore, Yin Ling Woo, Wei Zheng, Andrew Berchuck, Joellen M. Schildkraut, Linda E. Kelemen, Matthew L. Freedman

Obstetrics and Gynecology

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

12 Scopus citations

Abstract

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer.

Original language	English (US)
Pages (from-to)	467-481
Number of pages	15
Journal	Cancer Research
Volume	79
Issue number	3
DOIs	https://doi.org/10.1158/0008-5472.CAN-17-3864
State	Published - Feb 1 2019

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1158/0008-5472.CAN-17-3864

Cite this

Buckley, M. A., Woods, N. T., Tyrer, J. P., Mendoza-Fandiño, G., Lawrenson, K., Hazelett, D. J., Najafabadi, H. S., Gjyshi, A., Carvalho, R. S., Lyra, P. C., Coetzee, S. G., Shen, H. C., Yang, A. W., Earp, M. A., Yoder, S. J., Risch, H., Chenevix-Trench, G., Ramus, S. J., Phelan, C. M., ... Freedman, M. L. (2019). Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus. Cancer Research, 79(3), 467-481. https://doi.org/10.1158/0008-5472.CAN-17-3864

Buckley, MA, Woods, NT, Tyrer, JP, Mendoza-Fandiño, G, Lawrenson, K, Hazelett, DJ, Najafabadi, HS, Gjyshi, A, Carvalho, RS, Lyra, PC, Coetzee, SG, Shen, HC, Yang, AW, Earp, MA, Yoder, SJ, Risch, H, Chenevix-Trench, G, Ramus, SJ, Phelan, CM, Coetzee, GA, Noushmehr, H, Hughes, TR, Sellers, TA, Goode, EL, Pharoah, PD, Gayther, SA, Monteiro, ANA, Chen, YA, Fridley, BL, Aben, KKH, Kiemeney, LA, Anton-Culver, H, Ziogas, A, Bruinsma, F, Milne, RL, Bandera, EV, Giles, GG, Bean, YT, Pejovic, T, Beckmann, MW, Hein, A, Bjorge, L, Fasching, PA, Thomsen, LCV, Kopperud, RK, Bischof, K, Bogdanova, N, Dörk, T, Hillemanns, P, Brinton, LA, Wentzensen, N, Yang, H, Brooks-Wilson, A, Bunker, CH, Butzow, R, Nevanlinna, H, Pelttari, LM, Campbell, IG, Southey, MC, Modugno, F, Carty, K, Glasspool, R, McNeish, I, Paul, J, Siddiqui, N, Chang-Claude, J, Rudolph, A, Cook, LS, Cramer, DW, Terry, KL, Cunningham, JM, Cybulski, C, Gronwald, J, Jakubowska, A, Lubinski, J, Dansonka-Mieszkowska, A, Kupryjanczyk, J, Rzepecka, IK, Du Bois, A, Harter, P, Dicks, E, Song, H, Doherty, JA, Rossing, MA, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Gao, YT, Gentry-Maharaj, A, Goodman, MT, Thompson, PJ, Hasmad, HN, Teo, SH, Hildebrandt, MAT, Wu, X, Hogdall, E, Jensen, A, Kjaer, SK, Iversen, ES, Karlan, BY, Lester, J, Orsulic, S, Walsh, CS, Kelley, JL, Lambrechts, D, Lambrechts, S, Vergote, I, Lee, AW, Levine, DA, Liang, D, Lissowska, J, Lu, K, Lundvall, L, Massuger, LFAG, Van Altena, AM, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Moysich, KB, Ness, RB, Odunsi, K, Olson, SH, Orlow, I, Pike, MC, Pearce, CL, Wu, AH, Permuth, JB, Tsai, YY, Tworoger, SS, Poole, EM, Rosen, B, Shu, XO, Shvetsov, YB, Wilkens, LR, Sieh, W, Spiewankiewicz, B, Sucheston-Campbell, L, Thomsen, L, Wang-Gohrke, S, Whittemore, AS, Woo, YL, Zheng, W, Berchuck, A, Schildkraut, JM, Kelemen, LE & Freedman, ML 2019, 'Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus', Cancer Research, vol. 79, no. 3, pp. 467-481. https://doi.org/10.1158/0008-5472.CAN-17-3864

@article{2146a3066d20412386f6b88b926ec660,

title = "Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus",

abstract = "Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer.",

author = "Buckley, {Melissa A.} and Woods, {Nicholas T.} and Tyrer, {Jonathan P.} and Gustavo Mendoza-Fandi{\~n}o and Kate Lawrenson and Hazelett, {Dennis J.} and Najafabadi, {Hamed S.} and Anxhela Gjyshi and Carvalho, {Renato S.} and Lyra, {Paulo C.} and Coetzee, {Simon G.} and Shen, {Howard C.} and Yang, {Ally W.} and Earp, {Madalene A.} and Yoder, {Sean J.} and Harvey Risch and Georgia Chenevix-Trench and Ramus, {Susan J.} and Phelan, {Catherine M.} and Coetzee, {Gerhard A.} and Houtan Noushmehr and Hughes, {Timothy R.} and Sellers, {Thomas A.} and Goode, {Ellen L.} and Pharoah, {Paul D.} and Gayther, {Simon A.} and Monteiro, {Alvaro N.A.} and Chen, {Y. Ann} and Fridley, {Brooke L.} and Aben, {Katja K.H.} and Kiemeney, {Lambertus A.} and Hoda Anton-Culver and Argyrios Ziogas and Fiona Bruinsma and Milne, {Roger L.} and Bandera, {Elisa V.} and Giles, {Graham G.} and Bean, {Yukie T.} and Tanja Pejovic and Beckmann, {Matthias W.} and Alexander Hein and Line Bjorge and Fasching, {Peter A.} and Thomsen, {Liv C.V.} and Kopperud, {Reidun K.} and Katharina Bischof and Natalia Bogdanova and Thilo D{\"o}rk and Peter Hillemanns and Brinton, {Louise A.} and Nicolas Wentzensen and Hannah Yang and Angela Brooks-Wilson and Bunker, {Clareann H.} and Ralf Butzow and Heli Nevanlinna and Pelttari, {Liisa M.} and Campbell, {Ian G.} and Southey, {Melissa C.} and Francesmary Modugno and Karen Carty and Rosalind Glasspool and Ian McNeish and James Paul and Nadeem Siddiqui and Jenny Chang-Claude and Anja Rudolph and Cook, {Linda S.} and Cramer, {Daniel W.} and Terry, {Kathryn L.} and Cunningham, {Julie M.} and Cezary Cybulski and Jacek Gronwald and Anna Jakubowska and Jan Lubinski and Agnieszka Dansonka-Mieszkowska and Jolanta Kupryjanczyk and Rzepecka, {Iwona K.} and {Du Bois}, Andreas and Philipp Harter and Ed Dicks and Honglin Song and Doherty, {Jennifer A.} and Rossing, {Mary Anne} and Matthias D{\"u}rst and Easton, {Douglas F.} and Eccles, {Diana M.} and Edwards, {Robert P.} and Ekici, {Arif B.} and Gao, {Yu Tang} and Aleksandra Gentry-Maharaj and Goodman, {Marc T.} and Thompson, {Pamela J.} and Hasmad, {Hanis N.} and Teo, {Soo Hwang} and Hildebrandt, {Michelle A.T.} and Xifeng Wu and Estrid Hogdall and Allan Jensen and Kjaer, {Susanne K.} and Iversen, {Edwin S.} and Karlan, {Beth Y.} and Jenny Lester and Sandra Orsulic and Walsh, {Christine S.} and Kelley, {Joseph L.} and Diether Lambrechts and Sandrina Lambrechts and Ignace Vergote and Lee, {Alice W.} and Levine, {Douglas A.} and Dong Liang and Jolanta Lissowska and Karen Lu and Lene Lundvall and Massuger, {Leon F.A.G.} and {Van Altena}, {Anne M.} and Keitaro Matsuo and Valerie McGuire and McLaughlin, {John R.} and Usha Menon and Moysich, {Kirsten B.} and Ness, {Roberta B.} and Kunle Odunsi and Olson, {Sara H.} and Irene Orlow and Pike, {Malcolm C.} and Pearce, {Celeste L.} and Wu, {Anna H.} and Permuth, {Jennifer B.} and Tsai, {Ya Yu} and Tworoger, {Shelley S.} and Poole, {Elizabeth M.} and Barry Rosen and Shu, {Xiao Ou} and Shvetsov, {Yurii B.} and Wilkens, {Lynne R.} and Weiva Sieh and Beata Spiewankiewicz and Lara Sucheston-Campbell and Lotte Thomsen and Shan Wang-Gohrke and Whittemore, {Alice S.} and Woo, {Yin Ling} and Wei Zheng and Andrew Berchuck and Schildkraut, {Joellen M.} and Kelemen, {Linda E.} and Freedman, {Matthew L.}",

note = "Funding Information: We thank Alexandra Valle, Jiqiang Yao and Xueli Li for technical assistance and Anindya Dutta for helpful discussions. This work was supported by the following awards: NIH Genetic Association and Mechanisms in Oncology (GAME-ON) through NCI U19 (CA148112, to T.A. Sellers); K99/R00 (CA184415, to K. Lawrenson); and R01 (CA136924, to G.A. Coetzee), a grant from the Ovarian Cancer Research Foundation (258807, to S.A. Gayther), and in part by the Cancer Informatics, Proteomics and the Molecular Genomics Core Facilities at the Moffitt Cancer Center through its NCI CCSG grant (P30-CA76292, to T.A. Sellers). M.A. Buckley is an ARCS (Achievement Rewards for College Scientists) fellow and a recipient of the Ruth L. Kirschstein National Research Service Award (F31 CA165528). Funding of the constituent studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes for Health Research (MOP-86727); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A16561, C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/ A15589); the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health Labour and Welfare of Japan; Grants-in-Aid for Scientific Research on Priority Areas and Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports, Culture and Technology of Japan; Takeda Science Foundation; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P01-CA87969, P30-CA15083, P50-CA105009, P50-CA136393, P50-CA159981, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-A071966, UM1 CA186107, UM1 CA176726 and Intramural research funds); the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280, W81XWH-07-0449, W81XWH-10-1-02802); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the German Cancer Research Center (DKFZ); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital {"}Womens Health Theme,{"} the Royal Marsden Hospital; WorkSafeBC, and OvCaRe: British Columbia's Ovarian Cancer Research Team. This study made use of data generated by the Wellcome Trust Case Control consortium; funding for the project was provided by the Wellcome Trust under award 076113. Funding Information: We thank Alexandra Valle, Jiqiang Yao and Xueli Li for technical assistance and Anindya Dutta for helpful discussions. This work was supported by the following awards: NIH Genetic Association and Mechanisms in Oncology (GAME-ON) through NCI U19 (CA148112, to T.A. Sellers); K99/R00 (CA184415, to K. Lawrenson); and R01 (CA136924, to G.A. Coetzee), a grant from the Ovarian Cancer Research Foundation (258807, to S.A.Gayther), and in part by the Cancer Informatics, Proteomics and the Molecular Genomics Core Facilities at the Moffitt Cancer Center through its NCI CCSG grant (P30-CA76292, to T.A. Sellers). M.A. Buckley is an ARCS (Achievement Rewards for College Scientists) fellow and a recipient of the Ruth L. Kirschstein National Research Service Award (F31 CA165528). Funding of the constituent studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes for Health Research (MOP-86727); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A16561, C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/ A15589); the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health Labour and Welfare of Japan; Grants-in-Aid for Scientific Research on Priority Areas and Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports, Culture and Technology of Japan; Takeda Science Foundation; the L&S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P01-CA87969, P30-CA15083, P50-CA105009, P50-CA136393, P50-CA159981, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-A071966, UM1 CA186107, UM1 CA176726 and Intramural research funds); the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280, W81XWH-07-0449, W81XWH-10-1-02802); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the German Cancer Research Center (DKFZ); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital {"}Womens Health Theme{"}, the Royal Marsden Hospital; WorkSafeBC, and OvCaRe: British Columbia's Ovarian Cancer Research Team. This study made use of data generated by the Wellcome Trust Case Control consortium; funding for the project was provided by the Wellcome Trust under award 076113. Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",

year = "2019",

month = feb,

day = "1",

doi = "10.1158/0008-5472.CAN-17-3864",

language = "English (US)",

volume = "79",

pages = "467--481",

journal = "Cancer Research",

issn = "0008-5472",

number = "3",

}

TY - JOUR

T1 - Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus

AU - Buckley, Melissa A.

AU - Woods, Nicholas T.

AU - Tyrer, Jonathan P.

AU - Mendoza-Fandiño, Gustavo

AU - Lawrenson, Kate

AU - Hazelett, Dennis J.

AU - Najafabadi, Hamed S.

AU - Gjyshi, Anxhela

AU - Carvalho, Renato S.

AU - Lyra, Paulo C.

AU - Coetzee, Simon G.

AU - Shen, Howard C.

AU - Yang, Ally W.

AU - Earp, Madalene A.

AU - Yoder, Sean J.

AU - Risch, Harvey

AU - Chenevix-Trench, Georgia

AU - Ramus, Susan J.

AU - Phelan, Catherine M.

AU - Coetzee, Gerhard A.

AU - Noushmehr, Houtan

AU - Hughes, Timothy R.

AU - Sellers, Thomas A.

AU - Goode, Ellen L.

AU - Pharoah, Paul D.

AU - Gayther, Simon A.

AU - Monteiro, Alvaro N.A.

AU - Chen, Y. Ann

AU - Fridley, Brooke L.

AU - Aben, Katja K.H.

AU - Kiemeney, Lambertus A.

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Bruinsma, Fiona

AU - Milne, Roger L.

AU - Bandera, Elisa V.

AU - Giles, Graham G.

AU - Bean, Yukie T.

AU - Pejovic, Tanja

AU - Beckmann, Matthias W.

AU - Hein, Alexander

AU - Bjorge, Line

AU - Fasching, Peter A.

AU - Thomsen, Liv C.V.

AU - Kopperud, Reidun K.

AU - Bischof, Katharina

AU - Bogdanova, Natalia

AU - Dörk, Thilo

AU - Hillemanns, Peter

AU - Brinton, Louise A.

AU - Wentzensen, Nicolas

AU - Yang, Hannah

AU - Brooks-Wilson, Angela

AU - Bunker, Clareann H.

AU - Butzow, Ralf

AU - Nevanlinna, Heli

AU - Pelttari, Liisa M.

AU - Campbell, Ian G.

AU - Southey, Melissa C.

AU - Modugno, Francesmary

AU - Carty, Karen

AU - Glasspool, Rosalind

AU - McNeish, Ian

AU - Paul, James

AU - Siddiqui, Nadeem

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Cook, Linda S.

AU - Cramer, Daniel W.

AU - Terry, Kathryn L.

AU - Cunningham, Julie M.

AU - Cybulski, Cezary

AU - Gronwald, Jacek

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Dansonka-Mieszkowska, Agnieszka

AU - Kupryjanczyk, Jolanta

AU - Rzepecka, Iwona K.

AU - Du Bois, Andreas

AU - Harter, Philipp

AU - Dicks, Ed

AU - Song, Honglin

AU - Doherty, Jennifer A.

AU - Rossing, Mary Anne

AU - Dürst, Matthias

AU - Easton, Douglas F.

AU - Eccles, Diana M.

AU - Edwards, Robert P.

AU - Ekici, Arif B.

AU - Gao, Yu Tang

AU - Gentry-Maharaj, Aleksandra

AU - Goodman, Marc T.

AU - Thompson, Pamela J.

AU - Hasmad, Hanis N.

AU - Teo, Soo Hwang

AU - Hildebrandt, Michelle A.T.

AU - Wu, Xifeng

AU - Hogdall, Estrid

AU - Jensen, Allan

AU - Kjaer, Susanne K.

AU - Iversen, Edwin S.

AU - Karlan, Beth Y.

AU - Lester, Jenny

AU - Orsulic, Sandra

AU - Walsh, Christine S.

AU - Kelley, Joseph L.

AU - Lambrechts, Diether

AU - Lambrechts, Sandrina

AU - Vergote, Ignace

AU - Lee, Alice W.

AU - Levine, Douglas A.

AU - Liang, Dong

AU - Lissowska, Jolanta

AU - Lu, Karen

AU - Lundvall, Lene

AU - Massuger, Leon F.A.G.

AU - Van Altena, Anne M.

AU - Matsuo, Keitaro

AU - McGuire, Valerie

AU - McLaughlin, John R.

AU - Menon, Usha

AU - Moysich, Kirsten B.

AU - Ness, Roberta B.

AU - Odunsi, Kunle

AU - Olson, Sara H.

AU - Orlow, Irene

AU - Pike, Malcolm C.

AU - Pearce, Celeste L.

AU - Wu, Anna H.

AU - Permuth, Jennifer B.

AU - Tsai, Ya Yu

AU - Tworoger, Shelley S.

AU - Poole, Elizabeth M.

AU - Rosen, Barry

AU - Shu, Xiao Ou

AU - Shvetsov, Yurii B.

AU - Wilkens, Lynne R.

AU - Sieh, Weiva

AU - Spiewankiewicz, Beata

AU - Sucheston-Campbell, Lara

AU - Thomsen, Lotte

AU - Wang-Gohrke, Shan

AU - Whittemore, Alice S.

AU - Woo, Yin Ling

AU - Zheng, Wei

AU - Berchuck, Andrew

AU - Schildkraut, Joellen M.

AU - Kelemen, Linda E.

AU - Freedman, Matthew L.

N1 - Funding Information: We thank Alexandra Valle, Jiqiang Yao and Xueli Li for technical assistance and Anindya Dutta for helpful discussions. This work was supported by the following awards: NIH Genetic Association and Mechanisms in Oncology (GAME-ON) through NCI U19 (CA148112, to T.A. Sellers); K99/R00 (CA184415, to K. Lawrenson); and R01 (CA136924, to G.A. Coetzee), a grant from the Ovarian Cancer Research Foundation (258807, to S.A. Gayther), and in part by the Cancer Informatics, Proteomics and the Molecular Genomics Core Facilities at the Moffitt Cancer Center through its NCI CCSG grant (P30-CA76292, to T.A. Sellers). M.A. Buckley is an ARCS (Achievement Rewards for College Scientists) fellow and a recipient of the Ruth L. Kirschstein National Research Service Award (F31 CA165528). Funding of the constituent studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes for Health Research (MOP-86727); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A16561, C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/ A15589); the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health Labour and Welfare of Japan; Grants-in-Aid for Scientific Research on Priority Areas and Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports, Culture and Technology of Japan; Takeda Science Foundation; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P01-CA87969, P30-CA15083, P50-CA105009, P50-CA136393, P50-CA159981, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-A071966, UM1 CA186107, UM1 CA176726 and Intramural research funds); the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280, W81XWH-07-0449, W81XWH-10-1-02802); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the German Cancer Research Center (DKFZ); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital "Womens Health Theme," the Royal Marsden Hospital; WorkSafeBC, and OvCaRe: British Columbia's Ovarian Cancer Research Team. This study made use of data generated by the Wellcome Trust Case Control consortium; funding for the project was provided by the Wellcome Trust under award 076113. Funding Information: We thank Alexandra Valle, Jiqiang Yao and Xueli Li for technical assistance and Anindya Dutta for helpful discussions. This work was supported by the following awards: NIH Genetic Association and Mechanisms in Oncology (GAME-ON) through NCI U19 (CA148112, to T.A. Sellers); K99/R00 (CA184415, to K. Lawrenson); and R01 (CA136924, to G.A. Coetzee), a grant from the Ovarian Cancer Research Foundation (258807, to S.A.Gayther), and in part by the Cancer Informatics, Proteomics and the Molecular Genomics Core Facilities at the Moffitt Cancer Center through its NCI CCSG grant (P30-CA76292, to T.A. Sellers). M.A. Buckley is an ARCS (Achievement Rewards for College Scientists) fellow and a recipient of the Ruth L. Kirschstein National Research Service Award (F31 CA165528). Funding of the constituent studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes for Health Research (MOP-86727); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A16561, C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/ A15589); the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health Labour and Welfare of Japan; Grants-in-Aid for Scientific Research on Priority Areas and Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports, Culture and Technology of Japan; Takeda Science Foundation; the L&S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P01-CA87969, P30-CA15083, P50-CA105009, P50-CA136393, P50-CA159981, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-A071966, UM1 CA186107, UM1 CA176726 and Intramural research funds); the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280, W81XWH-07-0449, W81XWH-10-1-02802); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the German Cancer Research Center (DKFZ); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital "Womens Health Theme", the Royal Marsden Hospital; WorkSafeBC, and OvCaRe: British Columbia's Ovarian Cancer Research Team. This study made use of data generated by the Wellcome Trust Case Control consortium; funding for the project was provided by the Wellcome Trust under award 076113. Publisher Copyright: © 2018 American Association for Cancer Research.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer.

AB - Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer.

UR - http://www.scopus.com/inward/record.url?scp=85060941094&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060941094&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-17-3864

DO - 10.1158/0008-5472.CAN-17-3864

M3 - Article

C2 - 30487138

AN - SCOPUS:85060941094

SN - 0008-5472

VL - 79

SP - 467

EP - 481

JO - Cancer Research

JF - Cancer Research

IS - 3

ER -

Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this