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 & 129 others 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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 languageEnglish (US)
Pages (from-to)467-481
Number of pages15
JournalCancer Research
Volume79
Issue number3
DOIs
StatePublished - Feb 1 2019

Fingerprint

Matrix Attachment Regions
Ovarian Neoplasms
Single Nucleotide Polymorphism
Transcriptional Regulatory Elements
Genome-Wide Association Study
Consensus Sequence
Genes
Chromosomes
Alleles
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Buckley, M. A., Woods, N. T., Tyrer, J. P., Mendoza-Fandiño, G., Lawrenson, K., Hazelett, D. J., ... 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

Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus. / Buckley, Melissa A.; Woods, Nicholas T.; Tyrer, Jonathan P.; Mendoza-Fandiño, Gustavo; Lawrenson, Kate; Hazelett, Dennis J.; Najafabadi, Hamed S.; Gjyshi, Anxhela; Carvalho, Renato S.; Lyra, Paulo C.; Coetzee, Simon G.; Shen, Howard C.; Yang, Ally W.; Earp, Madalene A.; Yoder, Sean J.; Risch, Harvey; Chenevix-Trench, Georgia; Ramus, Susan J.; Phelan, Catherine M.; Coetzee, Gerhard A.; Noushmehr, Houtan; Hughes, Timothy R.; Sellers, Thomas A.; Goode, Ellen L; Pharoah, Paul D.; Gayther, Simon A.; Monteiro, Alvaro N.A.; Chen, Y. Ann; Fridley, Brooke L.; Aben, Katja K.H.; Kiemeney, Lambertus A.; Anton-Culver, Hoda; Ziogas, Argyrios; Bruinsma, Fiona; Milne, Roger L.; Bandera, Elisa V.; Giles, Graham G.; Bean, Yukie T.; Pejovic, Tanja; Beckmann, Matthias W.; Hein, Alexander; Bjorge, Line; Fasching, Peter A.; Thomsen, Liv C.V.; Kopperud, Reidun K.; Bischof, Katharina; Bogdanova, Natalia; Dörk, Thilo; Hillemanns, Peter; Brinton, Louise A.; Wentzensen, Nicolas; Yang, Hannah; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Nevanlinna, Heli; Pelttari, Liisa M.; Campbell, Ian G.; Southey, Melissa C.; Modugno, Francesmary; Carty, Karen; Glasspool, Rosalind; McNeish, Ian; Paul, James; Siddiqui, Nadeem; Chang-Claude, Jenny; Rudolph, Anja; Cook, Linda S.; Cramer, Daniel W.; Terry, Kathryn L.; Cunningham, Julie M; Cybulski, Cezary; Gronwald, Jacek; Jakubowska, Anna; Lubinski, Jan; Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.; Du Bois, Andreas; Harter, Philipp; Dicks, Ed; Song, Honglin; Doherty, Jennifer A.; Rossing, Mary Anne; Dürst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Gao, Yu Tang; Gentry-Maharaj, Aleksandra; Goodman, Marc T.; Thompson, Pamela J.; Hasmad, Hanis N.; Teo, Soo Hwang; Hildebrandt, Michelle A.T.; Wu, Xifeng; Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne K.; Iversen, Edwin S.; Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Walsh, Christine S.; Kelley, Joseph L.; Lambrechts, Diether; Lambrechts, Sandrina; Vergote, Ignace; Lee, Alice W.; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lundvall, Lene; Massuger, Leon F.A.G.; Van Altena, Anne M.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; Menon, Usha; Moysich, Kirsten B.; Ness, Roberta B.; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Pike, Malcolm C.; Pearce, Celeste L.; Wu, Anna H.; Permuth, Jennifer B.; Tsai, Ya Yu; Tworoger, Shelley S.; Poole, Elizabeth M.; Rosen, Barry; Shu, Xiao Ou; Shvetsov, Yurii B.; Wilkens, Lynne R.; Sieh, Weiva; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Thomsen, Lotte; Wang-Gohrke, Shan; Whittemore, Alice S.; Woo, Yin Ling; Zheng, Wei; Berchuck, Andrew; Schildkraut, Joellen M.; Kelemen, Linda E.; Freedman, Matthew L.

In: Cancer Research, Vol. 79, No. 3, 01.02.2019, p. 467-481.

Research output: Contribution to journalArticle

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
Buckley MA, Woods NT, Tyrer JP, Mendoza-Fandiño G, Lawrenson K, Hazelett DJ et al. Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus. Cancer Research. 2019 Feb 1;79(3):467-481. https://doi.org/10.1158/0008-5472.CAN-17-3864
Buckley, Melissa A. ; Woods, Nicholas T. ; Tyrer, Jonathan P. ; Mendoza-Fandiño, Gustavo ; Lawrenson, Kate ; Hazelett, Dennis J. ; Najafabadi, Hamed S. ; Gjyshi, Anxhela ; Carvalho, Renato S. ; Lyra, Paulo C. ; Coetzee, Simon G. ; Shen, Howard C. ; Yang, Ally W. ; Earp, Madalene A. ; Yoder, Sean J. ; Risch, Harvey ; Chenevix-Trench, Georgia ; Ramus, Susan J. ; Phelan, Catherine M. ; Coetzee, Gerhard A. ; Noushmehr, Houtan ; Hughes, Timothy R. ; Sellers, Thomas A. ; Goode, Ellen L ; Pharoah, Paul D. ; Gayther, Simon A. ; Monteiro, Alvaro N.A. ; Chen, Y. Ann ; Fridley, Brooke L. ; Aben, Katja K.H. ; Kiemeney, Lambertus A. ; Anton-Culver, Hoda ; Ziogas, Argyrios ; Bruinsma, Fiona ; Milne, Roger L. ; Bandera, Elisa V. ; Giles, Graham G. ; Bean, Yukie T. ; Pejovic, Tanja ; Beckmann, Matthias W. ; Hein, Alexander ; Bjorge, Line ; Fasching, Peter A. ; Thomsen, Liv C.V. ; Kopperud, Reidun K. ; Bischof, Katharina ; Bogdanova, Natalia ; Dörk, Thilo ; Hillemanns, Peter ; Brinton, Louise A. ; Wentzensen, Nicolas ; Yang, Hannah ; Brooks-Wilson, Angela ; Bunker, Clareann H. ; Butzow, Ralf ; Nevanlinna, Heli ; Pelttari, Liisa M. ; Campbell, Ian G. ; Southey, Melissa C. ; Modugno, Francesmary ; Carty, Karen ; Glasspool, Rosalind ; McNeish, Ian ; Paul, James ; Siddiqui, Nadeem ; Chang-Claude, Jenny ; Rudolph, Anja ; Cook, Linda S. ; Cramer, Daniel W. ; Terry, Kathryn L. ; Cunningham, Julie M ; Cybulski, Cezary ; Gronwald, Jacek ; Jakubowska, Anna ; Lubinski, Jan ; Dansonka-Mieszkowska, Agnieszka ; Kupryjanczyk, Jolanta ; Rzepecka, Iwona K. ; Du Bois, Andreas ; Harter, Philipp ; Dicks, Ed ; Song, Honglin ; Doherty, Jennifer A. ; Rossing, Mary Anne ; Dürst, Matthias ; Easton, Douglas F. ; Eccles, Diana M. ; Edwards, Robert P. ; Ekici, Arif B. ; Gao, Yu Tang ; Gentry-Maharaj, Aleksandra ; Goodman, Marc T. ; Thompson, Pamela J. ; Hasmad, Hanis N. ; Teo, Soo Hwang ; Hildebrandt, Michelle A.T. ; Wu, Xifeng ; Hogdall, Estrid ; Jensen, Allan ; Kjaer, Susanne K. ; Iversen, Edwin S. ; Karlan, Beth Y. ; Lester, Jenny ; Orsulic, Sandra ; Walsh, Christine S. ; Kelley, Joseph L. ; Lambrechts, Diether ; Lambrechts, Sandrina ; Vergote, Ignace ; Lee, Alice W. ; Levine, Douglas A. ; Liang, Dong ; Lissowska, Jolanta ; Lu, Karen ; Lundvall, Lene ; Massuger, Leon F.A.G. ; Van Altena, Anne M. ; Matsuo, Keitaro ; McGuire, Valerie ; McLaughlin, John R. ; Menon, Usha ; Moysich, Kirsten B. ; Ness, Roberta B. ; Odunsi, Kunle ; Olson, Sara H. ; Orlow, Irene ; Pike, Malcolm C. ; Pearce, Celeste L. ; Wu, Anna H. ; Permuth, Jennifer B. ; Tsai, Ya Yu ; Tworoger, Shelley S. ; Poole, Elizabeth M. ; Rosen, Barry ; Shu, Xiao Ou ; Shvetsov, Yurii B. ; Wilkens, Lynne R. ; Sieh, Weiva ; Spiewankiewicz, Beata ; Sucheston-Campbell, Lara ; Thomsen, Lotte ; Wang-Gohrke, Shan ; Whittemore, Alice S. ; Woo, Yin Ling ; Zheng, Wei ; Berchuck, Andrew ; Schildkraut, Joellen M. ; Kelemen, Linda E. ; Freedman, Matthew L. / Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus. In: Cancer Research. 2019 ; Vol. 79, No. 3. pp. 467-481.
@article{09e5499b221d4bcb9fc62a2c0e547808,
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.}",
year = "2019",
month = "2",
day = "1",
doi = "10.1158/0008-5472.CAN-17-3864",
language = "English (US)",
volume = "79",
pages = "467--481",
journal = "Cancer Research",
issn = "0008-5472",
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}

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.

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

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

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

M3 - Article

VL - 79

SP - 467

EP - 481

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 3

ER -