Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

N Orr; F Dudbridge; N Dryden; S Maguire; D Novo; E Perrakis; N Johnson; M Ghoussaini; J L Hopper; M C Southey; C Apicella; J Stone; M K Schmidt; A Broeks; L J Van't Veer; F B Hogervorst; P A Fasching; L Haeberle; A B Ekici; M W Beckmann; L Gibson; Z Aitken; H Warren; E Sawyer; I Tomlinson; M J Kerin; N Miller; B Burwinkel; F Marme; A Schneeweiss; C Sohn; P Guenel; T Truong; E Cordina-Duverger; M Sanchez; S E Bojesen; B G Nordestgaard; S F Nielsen; H Flyger; J Benitez; M P Zamora; J I Arias Perez; P Menendez; H Anton-Culver; S L Neuhausen; H Brenner; A K Dieffenbach; V Arndt; C Stegmaier; U Hamann; H Brauch; C Justenhoven; T Bruning; Y D Ko; H Nevanlinna; K Aittomaki; C Blomqvist; S Khan; N Bogdanova; T Dork; A Lindblom; S Margolin; A Mannermaa; V Kataja; V M Kosma; J M Hartikainen; G Chenevix-Trench; J Beesley; D Lambrechts; M Moisse; G Floris; B Beuselinck; J Chang-Claude; A Rudolph; P Seibold; D Flesch-Janys; P Radice; P Peterlongo; B Peissel; V Pensotti; F J Couch; J E Olson; S Slettedahl; C Vachon; G G Giles; R L Milne; C McLean; C A Haiman; B E Henderson; F Schumacher; L Le Marchand; J Simard; M S Goldberg; F Labreche; M Dumont; V Kristensen; G G Alnaes; S Nord; A L Borresen-Dale; W Zheng; S Deming-Halverson; M Shrubsole; J Long; R Winqvist; K Pylkas; A Jukkola-Vuorinen; M Grip; I L Andrulis; J A Knight; G Glendon; S Tchatchou; P Devilee; R A Tollenaar; C M Seynaeve; C J Van Asperen; M Garcia-Closas; J Figueroa; S J Chanock; J Lissowska; K Czene; H Darabi; M Eriksson; D Klevebring; M J Hooning; A Hollestelle; C H van Deurzen; M Kriege; P Hall; J Li; J Liu; K Humphreys; A Cox; S S Cross; M W Reed; P D Pharoah; A M Dunning; M Shah; B J Perkins; A Jakubowska; J Lubinski; K Jaworska-Bieniek; K Durda; A Ashworth; A Swerdlow; M Jones; M J Schoemaker; A Meindl; R K Schmutzler; C Olswold; S Slager; A E Toland; D Yannoukakos; K Muir; A Lophatananon; S Stewart-Brown; P Siriwanarangsan; K Matsuo; H Ito; H Iwata; J Ishiguro; A H Wu; C C Tseng; D Van Den Berg; D O Stram; S H Teo; C H Yip; P Kang; M K Ikram; X O Shu; W Lu; Y T Gao; H Cai; D Kang; J Y Choi; S K Park; D Y Noh; M Hartman; H Miao; W Y Lim; S C Lee; S Sangrajrang; V Gaborieau; P Brennan; J McKay; P E Wu; M F Hou; J C Yu; C Y Shen; W Blot; Q Cai; L B Signorello; C Luccarini; C Bayes; S Ahmed; M Maranian; C S Healey; A Gonzalez-Neira; G Pita; M R Alonso; N Alvarez; D Herrero; D C Tessier; D Vincent; F Bacot; D J Hunter; S Lindstrom; J Dennis; K Michailidou; M K Bolla; D F Easton; I dos Santos Silva; O Fletcher; J Peto

doi:DOI:10.1093/hmg/ddv035

Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

N Orr, F Dudbridge, N Dryden, S Maguire, D Novo, E Perrakis, N Johnson, M Ghoussaini, J L Hopper, M C Southey, C Apicella, J Stone, M K Schmidt, A Broeks, L J Van't Veer, F B Hogervorst, P A Fasching, L Haeberle, A B Ekici, M W BeckmannL Gibson, Z Aitken, H Warren, E Sawyer, I Tomlinson, M J Kerin, N Miller, B Burwinkel, F Marme, A Schneeweiss, C Sohn, P Guenel, T Truong, E Cordina-Duverger, M Sanchez, S E Bojesen, B G Nordestgaard, S F Nielsen, H Flyger, J Benitez, M P Zamora, J I Arias Perez, P Menendez, H Anton-Culver, S L Neuhausen, H Brenner, A K Dieffenbach, V Arndt, C Stegmaier, U Hamann, H Brauch, C Justenhoven, T Bruning, Y D Ko, H Nevanlinna, K Aittomaki, C Blomqvist, S Khan, N Bogdanova, T Dork, A Lindblom, S Margolin, A Mannermaa, V Kataja, V M Kosma, J M Hartikainen, G Chenevix-Trench, J Beesley, D Lambrechts, M Moisse, G Floris, B Beuselinck, J Chang-Claude, A Rudolph, P Seibold, D Flesch-Janys, P Radice, P Peterlongo, B Peissel, V Pensotti, F J Couch, J E Olson, S Slettedahl, C Vachon, G G Giles, R L Milne, C McLean, C A Haiman, B E Henderson, F Schumacher, L Le Marchand, J Simard, M S Goldberg, F Labreche, M Dumont, V Kristensen, G G Alnaes, S Nord, A L Borresen-Dale, W Zheng, S Deming-Halverson, M Shrubsole, J Long, R Winqvist, K Pylkas, A Jukkola-Vuorinen, M Grip, I L Andrulis, J A Knight, G Glendon, S Tchatchou, P Devilee, R A Tollenaar, C M Seynaeve, C J Van Asperen, M Garcia-Closas, J Figueroa, S J Chanock, J Lissowska, K Czene, H Darabi, M Eriksson, D Klevebring, M J Hooning, A Hollestelle, C H van Deurzen, M Kriege, P Hall, J Li, J Liu, K Humphreys, A Cox, S S Cross, M W Reed, P D Pharoah, A M Dunning, M Shah, B J Perkins, A Jakubowska, J Lubinski, K Jaworska-Bieniek, K Durda, A Ashworth, A Swerdlow, M Jones, M J Schoemaker, A Meindl, R K Schmutzler, C Olswold, S Slager, A E Toland, D Yannoukakos, K Muir, A Lophatananon, S Stewart-Brown, P Siriwanarangsan, K Matsuo, H Ito, H Iwata, J Ishiguro, A H Wu, C C Tseng, D Van Den Berg, D O Stram, S H Teo, C H Yip, P Kang, M K Ikram, X O Shu, W Lu, Y T Gao, H Cai, D Kang, J Y Choi, S K Park, D Y Noh, M Hartman, H Miao, W Y Lim, S C Lee, S Sangrajrang, V Gaborieau, P Brennan, J McKay, P E Wu, M F Hou, J C Yu, C Y Shen, W Blot, Q Cai, L B Signorello, C Luccarini, C Bayes, S Ahmed, M Maranian, C S Healey, A Gonzalez-Neira, G Pita, M R Alonso, N Alvarez, D Herrero, D C Tessier, D Vincent, F Bacot, D J Hunter, S Lindstrom, J Dennis, K Michailidou, M K Bolla, D F Easton, I dos Santos Silva, O Fletcher, J Peto

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

Abstract

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans approximately 14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 x 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-alpha, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

Original language	English
Pages (from-to)	2966-84
Number of pages	2881
Journal	Hum Mol Genet
Volume	24
Issue number	10
DOIs	https://doi.org/DOI:10.1093/hmg/ddv035
Publication status	Published - 2015

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DOI:10.1093/hmg/ddv035

Cite this

Orr, N., Dudbridge, F., Dryden, N., Maguire, S., Novo, D., Perrakis, E., Johnson, N., Ghoussaini, M., Hopper, J. L., Southey, M. C., Apicella, C., Stone, J., Schmidt, M. K., Broeks, A., Van't Veer, L. J., Hogervorst, F. B., Fasching, P. A., Haeberle, L., Ekici, A. B., ... Peto, J. (2015). Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2. Hum Mol Genet, 24(10), 2966-84. https://doi.org/DOI:10.1093/hmg/ddv035

@article{26cd1d6a02c74560b27c4e56522a6f2f,

title = "Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2",

abstract = "We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans approximately 14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 x 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-alpha, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.",

author = "N Orr and F Dudbridge and N Dryden and S Maguire and D Novo and E Perrakis and N Johnson and M Ghoussaini and Hopper, {J L} and Southey, {M C} and C Apicella and J Stone and Schmidt, {M K} and A Broeks and {Van't Veer}, {L J} and Hogervorst, {F B} and Fasching, {P A} and L Haeberle and Ekici, {A B} and Beckmann, {M W} and L Gibson and Z Aitken and H Warren and E Sawyer and I Tomlinson and Kerin, {M J} and N Miller and B Burwinkel and F Marme and A Schneeweiss and C Sohn and P Guenel and T Truong and E Cordina-Duverger and M Sanchez and Bojesen, {S E} and Nordestgaard, {B G} and Nielsen, {S F} and H Flyger and J Benitez and Zamora, {M P} and {Arias Perez}, {J I} and P Menendez and H Anton-Culver and Neuhausen, {S L} and H Brenner and Dieffenbach, {A K} and V Arndt and C Stegmaier and U Hamann and H Brauch and C Justenhoven and T Bruning and Ko, {Y D} and H Nevanlinna and K Aittomaki and C Blomqvist and S Khan and N Bogdanova and T Dork and A Lindblom and S Margolin and A Mannermaa and V Kataja and Kosma, {V M} and Hartikainen, {J M} and G Chenevix-Trench and J Beesley and D Lambrechts and M Moisse and G Floris and B Beuselinck and J Chang-Claude and A Rudolph and P Seibold and D Flesch-Janys and P Radice and P Peterlongo and B Peissel and V Pensotti and Couch, {F J} and Olson, {J E} and S Slettedahl and C Vachon and Giles, {G G} and Milne, {R L} and C McLean and Haiman, {C A} and Henderson, {B E} and F Schumacher and {Le Marchand}, L and J Simard and Goldberg, {M S} and F Labreche and M Dumont and V Kristensen and Alnaes, {G G} and S Nord and Borresen-Dale, {A L} and W Zheng and S Deming-Halverson and M Shrubsole and J Long and R Winqvist and K Pylkas and A Jukkola-Vuorinen and M Grip and Andrulis, {I L} and Knight, {J A} and G Glendon and S Tchatchou and P Devilee and Tollenaar, {R A} and Seynaeve, {C M} and {Van Asperen}, {C J} and M Garcia-Closas and J Figueroa and Chanock, {S J} and J Lissowska and K Czene and H Darabi and M Eriksson and D Klevebring and Hooning, {M J} and A Hollestelle and {van Deurzen}, {C H} and M Kriege and P Hall and J Li and J Liu and K Humphreys and A Cox and Cross, {S S} and Reed, {M W} and Pharoah, {P D} and Dunning, {A M} and M Shah and Perkins, {B J} and A Jakubowska and J Lubinski and K Jaworska-Bieniek and K Durda and A Ashworth and A Swerdlow and M Jones and Schoemaker, {M J} and A Meindl and Schmutzler, {R K} and C Olswold and S Slager and Toland, {A E} and D Yannoukakos and K Muir and A Lophatananon and S Stewart-Brown and P Siriwanarangsan and K Matsuo and H Ito and H Iwata and J Ishiguro and Wu, {A H} and Tseng, {C C} and {Van Den Berg}, D and Stram, {D O} and Teo, {S H} and Yip, {C H} and P Kang and Ikram, {M K} and Shu, {X O} and W Lu and Gao, {Y T} and H Cai and D Kang and Choi, {J Y} and Park, {S K} and Noh, {D Y} and M Hartman and H Miao and Lim, {W Y} and Lee, {S C} and S Sangrajrang and V Gaborieau and P Brennan and J McKay and Wu, {P E} and Hou, {M F} and Yu, {J C} and Shen, {C Y} and W Blot and Q Cai and Signorello, {L B} and C Luccarini and C Bayes and S Ahmed and M Maranian and Healey, {C S} and A Gonzalez-Neira and G Pita and Alonso, {M R} and N Alvarez and D Herrero and Tessier, {D C} and D Vincent and F Bacot and Hunter, {D J} and S Lindstrom and J Dennis and K Michailidou and Bolla, {M K} and Easton, {D F} and {dos Santos Silva}, I and O Fletcher and J Peto",

note = "Orr, Nick Dudbridge, Frank Dryden, Nicola Maguire, Sarah Novo, Daniela Perrakis, Eleni Johnson, Nichola Ghoussaini, Maya Hopper, John L Southey, Melissa C Apicella, Carmel Stone, Jennifer Schmidt, Marjanka K Broeks, Annegien Van't Veer, Laura J Hogervorst, Frans B Fasching, Peter A Haeberle, Lothar Ekici, Arif B Beckmann, Matthias W Gibson, Lorna Aitken, Zoe Warren, Helen Sawyer, Elinor Tomlinson, Ian Kerin, Michael J Miller, Nicola Burwinkel, Barbara Marme, Frederik Schneeweiss, Andreas Sohn, Chistof Guenel, Pascal Truong, Therese Cordina-Duverger, Emilie Sanchez, Marie Bojesen, Stig E Nordestgaard, Borge G Nielsen, Sune F Flyger, Henrik Benitez, Javier Zamora, Maria Pilar Arias Perez, Jose Ignacio Menendez, Primitiva Anton-Culver, Hoda Neuhausen, Susan L Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa Hamann, Ute Brauch, Hiltrud Justenhoven, Christina Bruning, Thomas Ko, Yon-Dschun Nevanlinna, Heli Aittomaki, Kristiina Blomqvist, Carl Khan, Sofia Bogdanova, Natalia Dork, Thilo Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M Chenevix-Trench, Georgia Beesley, Jonathan Lambrechts, Diether Moisse, Matthieu Floris, Guiseppe Beuselinck, Benoit Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Radice, Paolo Peterlongo, Paolo Peissel, Bernard Pensotti, Valeria Couch, Fergus J Olson, Janet E Slettedahl, Seth Vachon, Celine Giles, Graham G Milne, Roger L McLean, Catriona Haiman, Christopher A Henderson, Brian E Schumacher, Fredrick Le Marchand, Loic Simard, Jacques Goldberg, Mark S Labreche, France Dumont, Martine Kristensen, Vessela Alnaes, Grethe Grenaker Nord, Silje Borresen-Dale, Anne-Lise Zheng, Wei Deming-Halverson, Sandra Shrubsole, Martha Long, Jirong Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi Andrulis, Irene L Knight, Julia A Glendon, Gord Tchatchou, Sandrine Devilee, Peter Tollenaar, Robertus A E M Seynaeve, Caroline M Van Asperen, Christi J Garcia-Closas, Montserrat Figueroa, Jonine Chanock, Stephen J Lissowska, Jolanta Czene, Kamila Darabi, Hatef Eriksson, Mikael Klevebring, Daniel Hooning, Maartje J Hollestelle, Antoinette van Deurzen, Carolien H M Kriege, Mieke Hall, Per Li, Jingmei Liu, Jianjun Humphreys, Keith Cox, Angela Cross, Simon S Reed, Malcolm W R Pharoah, Paul D P Dunning, Alison M Shah, Mitul Perkins, Barbara J Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katarzyna Ashworth, Alan Swerdlow, Anthony Jones, Michael Schoemaker, Minouk J Meindl, Alfons Schmutzler, Rita K Olswold, Curtis Slager, Susan Toland, Amanda E Yannoukakos, Drakoulis Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Matsuo, Keitaro Ito, Hidema Iwata, Hiroji Ishiguro, Junko Wu, Anna H Tseng, Chiu-Chen Van Den Berg, David Stram, Daniel O Teo, Soo Hwang Yip, Cheng Har Kang, Peter Ikram, Mohammad Kamran Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Cai, Hui Kang, Daehee Choi, Ji-Yeob Park, Sue K Noh, Dong-Young Hartman, Mikael Miao, Hui Lim, Wei Yen Lee, Soo Chin Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul Mckay, James Wu, Pei-Ei Hou, Ming-Feng Yu, Jyh-Cherng Shen, Chen-Yang Blot, William Cai, Qiuyin Signorello, Lisa B Luccarini, Craig Bayes, Caroline Ahmed, Shahana Maranian, Mel Healey, Catherine S Gonzalez-Neira, Anna Pita, Guillermo Alonso, M Rosario Alvarez, Nuria Herrero, Daniel Tessier, Daniel C Vincent, Daniel Bacot, Francois Hunter, David J Lindstrom, Sara Dennis, Joe Michailidou, Kyriaki Bolla, Manjeet K Easton, Douglas F dos Santos Silva, Isabel Fletcher, Olivia Peto, Julian GENICA Network kConFab Investigators Australian Ovarian Cancer Study Group 1U19 CA148065/CA/NCI NIH HHS/United States 1U19 CA148112/CA/NCI NIH HHS/United States 1U19 CA148537/CA/NCI NIH HHS/United States C12292/A11174/Cancer Research UK/United Kingdom C1281/A12014/Cancer Research UK/United Kingdom C1287/A10118/Cancer Research UK/United Kingdom C1287/A10710/Cancer Research UK/United Kingdom C1287/A12014/Cancer Research UK/United Kingdom C490/A10124/Cancer Research UK/United Kingdom C5047/A10692/Cancer Research UK/United Kingdom C5047/A15007/Cancer Research UK/United Kingdom C5047A8384/Cancer Research UK/United Kingdom C8197/A16565/Cancer Research UK/United Kingdom CA116167/CA/NCI NIH HHS/United States CA116201/CA/NCI NIH HHS/United States CA128978/CA/NCI NIH HHS/United States CA176785/CA/NCI NIH HHS/United States N01 CN25403/CN/NCI NIH HHS/United States P30 CA015083/CA/NCI NIH HHS/United States P30 CA16056/CA/NCI NIH HHS/United States P30 CA68485/CA/NCI NIH HHS/United States P50 CA116201/CA/NCI NIH HHS/United States R01 CA092447/CA/NCI NIH HHS/United States R01 CA77398/CA/NCI NIH HHS/United States R01CA100374/CA/NCI NIH HHS/United States R01CA148667/CA/NCI NIH HHS/United States R01CA64277/CA/NCI NIH HHS/United States R37CA70867/CA/NCI NIH HHS/United States U01 CA116167/CA/NCI NIH HHS/United States U19 CA148065/CA/NCI NIH HHS/United States UM1CA164920/CA/NCI NIH HHS/United States Canadian Institutes of Health Research/Canada Intramural NIH HHS/United States Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. England Human molecular genetics Hum Mol Genet. 2015 May 15;24(10):2966-84. doi: 10.1093/hmg/ddv035. Epub 2015 Feb 4.",

year = "2015",

doi = "DOI:10.1093/hmg/ddv035",

language = "English",

volume = "24",

pages = "2966--84",

journal = "Hum Mol Genet",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "10",

}

Orr, N, Dudbridge, F, Dryden, N, Maguire, S, Novo, D, Perrakis, E, Johnson, N, Ghoussaini, M, Hopper, JL, Southey, MC, Apicella, C, Stone, J, Schmidt, MK, Broeks, A, Van't Veer, LJ, Hogervorst, FB, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Gibson, L, Aitken, Z, Warren, H, Sawyer, E, Tomlinson, I, Kerin, MJ, Miller, N, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Guenel, P, Truong, T, Cordina-Duverger, E, Sanchez, M, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Benitez, J, Zamora, MP, Arias Perez, JI, Menendez, P, Anton-Culver, H, Neuhausen, SL, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Hamann, U, Brauch, H, Justenhoven, C, Bruning, T, Ko, YD, Nevanlinna, H, Aittomaki, K, Blomqvist, C, Khan, S, Bogdanova, N, Dork, T, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Chenevix-Trench, G, Beesley, J, Lambrechts, D, Moisse, M, Floris, G, Beuselinck, B, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Radice, P, Peterlongo, P, Peissel, B, Pensotti, V, Couch, FJ, Olson, JE, Slettedahl, S, Vachon, C, Giles, GG, Milne, RL, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Kristensen, V, Alnaes, GG, Nord, S, Borresen-Dale, AL, Zheng, W, Deming-Halverson, S, Shrubsole, M, Long, J, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, RA, Seynaeve, CM, Van Asperen, CJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Hooning, MJ, Hollestelle, A, van Deurzen, CH, Kriege, M, Hall, P, Li, J, Liu, J, Humphreys, K, Cox, A, Cross, SS, Reed, MW, Pharoah, PD, Dunning, AM, Shah, M, Perkins, BJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Ashworth, A, Swerdlow, A, Jones, M, Schoemaker, MJ, Meindl, A, Schmutzler, RK, Olswold, C, Slager, S, Toland, AE, Yannoukakos, D, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Matsuo, K, Ito, H, Iwata, H, Ishiguro, J, Wu, AH, Tseng, CC, Van Den Berg, D, Stram, DO, Teo, SH, Yip, CH, Kang, P, Ikram, MK, Shu, XO, Lu, W, Gao, YT, Cai, H, Kang, D, Choi, JY, Park, SK, Noh, DY, Hartman, M, Miao, H, Lim, WY, Lee, SC, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Wu, PE, Hou, MF, Yu, JC, Shen, CY, Blot, W, Cai, Q, Signorello, LB, Luccarini, C, Bayes, C, Ahmed, S, Maranian, M, Healey, CS, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Hunter, DJ, Lindstrom, S, Dennis, J, Michailidou, K, Bolla, MK, Easton, DF, dos Santos Silva, I, Fletcher, O & Peto, J 2015, 'Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2', Hum Mol Genet, vol. 24, no. 10, pp. 2966-84. https://doi.org/DOI:10.1093/hmg/ddv035

TY - JOUR

T1 - Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

AU - Orr, N

AU - Dudbridge, F

AU - Dryden, N

AU - Maguire, S

AU - Novo, D

AU - Perrakis, E

AU - Johnson, N

AU - Ghoussaini, M

AU - Hopper, J L

AU - Southey, M C

AU - Apicella, C

AU - Stone, J

AU - Schmidt, M K

AU - Broeks, A

AU - Van't Veer, L J

AU - Hogervorst, F B

AU - Fasching, P A

AU - Haeberle, L

AU - Ekici, A B

AU - Beckmann, M W

AU - Gibson, L

AU - Aitken, Z

AU - Warren, H

AU - Sawyer, E

AU - Tomlinson, I

AU - Kerin, M J

AU - Miller, N

AU - Burwinkel, B

AU - Marme, F

AU - Schneeweiss, A

AU - Sohn, C

AU - Guenel, P

AU - Truong, T

AU - Cordina-Duverger, E

AU - Sanchez, M

AU - Bojesen, S E

AU - Nordestgaard, B G

AU - Nielsen, S F

AU - Flyger, H

AU - Benitez, J

AU - Zamora, M P

AU - Arias Perez, J I

AU - Menendez, P

AU - Anton-Culver, H

AU - Neuhausen, S L

AU - Brenner, H

AU - Dieffenbach, A K

AU - Arndt, V

AU - Stegmaier, C

AU - Hamann, U

AU - Brauch, H

AU - Justenhoven, C

AU - Bruning, T

AU - Ko, Y D

AU - Nevanlinna, H

AU - Aittomaki, K

AU - Blomqvist, C

AU - Khan, S

AU - Bogdanova, N

AU - Dork, T

AU - Lindblom, A

AU - Margolin, S

AU - Mannermaa, A

AU - Kataja, V

AU - Kosma, V M

AU - Hartikainen, J M

AU - Chenevix-Trench, G

AU - Beesley, J

AU - Lambrechts, D

AU - Moisse, M

AU - Floris, G

AU - Beuselinck, B

AU - Chang-Claude, J

AU - Rudolph, A

AU - Seibold, P

AU - Flesch-Janys, D

AU - Radice, P

AU - Peterlongo, P

AU - Peissel, B

AU - Pensotti, V

AU - Couch, F J

AU - Olson, J E

AU - Slettedahl, S

AU - Vachon, C

AU - Giles, G G

AU - Milne, R L

AU - McLean, C

AU - Haiman, C A

AU - Henderson, B E

AU - Schumacher, F

AU - Le Marchand, L

AU - Simard, J

AU - Goldberg, M S

AU - Labreche, F

AU - Dumont, M

AU - Kristensen, V

AU - Alnaes, G G

AU - Nord, S

AU - Borresen-Dale, A L

AU - Zheng, W

AU - Deming-Halverson, S

AU - Shrubsole, M

AU - Long, J

AU - Winqvist, R

AU - Pylkas, K

AU - Jukkola-Vuorinen, A

AU - Grip, M

AU - Andrulis, I L

AU - Knight, J A

AU - Glendon, G

AU - Tchatchou, S

AU - Devilee, P

AU - Tollenaar, R A

AU - Seynaeve, C M

AU - Van Asperen, C J

AU - Garcia-Closas, M

AU - Figueroa, J

AU - Chanock, S J

AU - Lissowska, J

AU - Czene, K

AU - Darabi, H

AU - Eriksson, M

AU - Klevebring, D

AU - Hooning, M J

AU - Hollestelle, A

AU - van Deurzen, C H

AU - Kriege, M

AU - Hall, P

AU - Li, J

AU - Liu, J

AU - Humphreys, K

AU - Cox, A

AU - Cross, S S

AU - Reed, M W

AU - Pharoah, P D

AU - Dunning, A M

AU - Shah, M

AU - Perkins, B J

AU - Jakubowska, A

AU - Lubinski, J

AU - Jaworska-Bieniek, K

AU - Durda, K

AU - Ashworth, A

AU - Swerdlow, A

AU - Jones, M

AU - Schoemaker, M J

AU - Meindl, A

AU - Schmutzler, R K

AU - Olswold, C

AU - Slager, S

AU - Toland, A E

AU - Yannoukakos, D

AU - Muir, K

AU - Lophatananon, A

AU - Stewart-Brown, S

AU - Siriwanarangsan, P

AU - Matsuo, K

AU - Ito, H

AU - Iwata, H

AU - Ishiguro, J

AU - Wu, A H

AU - Tseng, C C

AU - Van Den Berg, D

AU - Stram, D O

AU - Teo, S H

AU - Yip, C H

AU - Kang, P

AU - Ikram, M K

AU - Shu, X O

AU - Lu, W

AU - Gao, Y T

AU - Cai, H

AU - Kang, D

AU - Choi, J Y

AU - Park, S K

AU - Noh, D Y

AU - Hartman, M

AU - Miao, H

AU - Lim, W Y

AU - Lee, S C

AU - Sangrajrang, S

AU - Gaborieau, V

AU - Brennan, P

AU - McKay, J

AU - Wu, P E

AU - Hou, M F

AU - Yu, J C

AU - Shen, C Y

AU - Blot, W

AU - Cai, Q

AU - Signorello, L B

AU - Luccarini, C

AU - Bayes, C

AU - Ahmed, S

AU - Maranian, M

AU - Healey, C S

AU - Gonzalez-Neira, A

AU - Pita, G

AU - Alonso, M R

AU - Alvarez, N

AU - Herrero, D

AU - Tessier, D C

AU - Vincent, D

AU - Bacot, F

AU - Hunter, D J

AU - Lindstrom, S

AU - Dennis, J

AU - Michailidou, K

AU - Bolla, M K

AU - Easton, D F

AU - dos Santos Silva, I

AU - Fletcher, O

AU - Peto, J

N1 - Orr, Nick Dudbridge, Frank Dryden, Nicola Maguire, Sarah Novo, Daniela Perrakis, Eleni Johnson, Nichola Ghoussaini, Maya Hopper, John L Southey, Melissa C Apicella, Carmel Stone, Jennifer Schmidt, Marjanka K Broeks, Annegien Van't Veer, Laura J Hogervorst, Frans B Fasching, Peter A Haeberle, Lothar Ekici, Arif B Beckmann, Matthias W Gibson, Lorna Aitken, Zoe Warren, Helen Sawyer, Elinor Tomlinson, Ian Kerin, Michael J Miller, Nicola Burwinkel, Barbara Marme, Frederik Schneeweiss, Andreas Sohn, Chistof Guenel, Pascal Truong, Therese Cordina-Duverger, Emilie Sanchez, Marie Bojesen, Stig E Nordestgaard, Borge G Nielsen, Sune F Flyger, Henrik Benitez, Javier Zamora, Maria Pilar Arias Perez, Jose Ignacio Menendez, Primitiva Anton-Culver, Hoda Neuhausen, Susan L Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa Hamann, Ute Brauch, Hiltrud Justenhoven, Christina Bruning, Thomas Ko, Yon-Dschun Nevanlinna, Heli Aittomaki, Kristiina Blomqvist, Carl Khan, Sofia Bogdanova, Natalia Dork, Thilo Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M Chenevix-Trench, Georgia Beesley, Jonathan Lambrechts, Diether Moisse, Matthieu Floris, Guiseppe Beuselinck, Benoit Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Radice, Paolo Peterlongo, Paolo Peissel, Bernard Pensotti, Valeria Couch, Fergus J Olson, Janet E Slettedahl, Seth Vachon, Celine Giles, Graham G Milne, Roger L McLean, Catriona Haiman, Christopher A Henderson, Brian E Schumacher, Fredrick Le Marchand, Loic Simard, Jacques Goldberg, Mark S Labreche, France Dumont, Martine Kristensen, Vessela Alnaes, Grethe Grenaker Nord, Silje Borresen-Dale, Anne-Lise Zheng, Wei Deming-Halverson, Sandra Shrubsole, Martha Long, Jirong Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi Andrulis, Irene L Knight, Julia A Glendon, Gord Tchatchou, Sandrine Devilee, Peter Tollenaar, Robertus A E M Seynaeve, Caroline M Van Asperen, Christi J Garcia-Closas, Montserrat Figueroa, Jonine Chanock, Stephen J Lissowska, Jolanta Czene, Kamila Darabi, Hatef Eriksson, Mikael Klevebring, Daniel Hooning, Maartje J Hollestelle, Antoinette van Deurzen, Carolien H M Kriege, Mieke Hall, Per Li, Jingmei Liu, Jianjun Humphreys, Keith Cox, Angela Cross, Simon S Reed, Malcolm W R Pharoah, Paul D P Dunning, Alison M Shah, Mitul Perkins, Barbara J Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katarzyna Ashworth, Alan Swerdlow, Anthony Jones, Michael Schoemaker, Minouk J Meindl, Alfons Schmutzler, Rita K Olswold, Curtis Slager, Susan Toland, Amanda E Yannoukakos, Drakoulis Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Matsuo, Keitaro Ito, Hidema Iwata, Hiroji Ishiguro, Junko Wu, Anna H Tseng, Chiu-Chen Van Den Berg, David Stram, Daniel O Teo, Soo Hwang Yip, Cheng Har Kang, Peter Ikram, Mohammad Kamran Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Cai, Hui Kang, Daehee Choi, Ji-Yeob Park, Sue K Noh, Dong-Young Hartman, Mikael Miao, Hui Lim, Wei Yen Lee, Soo Chin Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul Mckay, James Wu, Pei-Ei Hou, Ming-Feng Yu, Jyh-Cherng Shen, Chen-Yang Blot, William Cai, Qiuyin Signorello, Lisa B Luccarini, Craig Bayes, Caroline Ahmed, Shahana Maranian, Mel Healey, Catherine S Gonzalez-Neira, Anna Pita, Guillermo Alonso, M Rosario Alvarez, Nuria Herrero, Daniel Tessier, Daniel C Vincent, Daniel Bacot, Francois Hunter, David J Lindstrom, Sara Dennis, Joe Michailidou, Kyriaki Bolla, Manjeet K Easton, Douglas F dos Santos Silva, Isabel Fletcher, Olivia Peto, Julian GENICA Network kConFab Investigators Australian Ovarian Cancer Study Group 1U19 CA148065/CA/NCI NIH HHS/United States 1U19 CA148112/CA/NCI NIH HHS/United States 1U19 CA148537/CA/NCI NIH HHS/United States C12292/A11174/Cancer Research UK/United Kingdom C1281/A12014/Cancer Research UK/United Kingdom C1287/A10118/Cancer Research UK/United Kingdom C1287/A10710/Cancer Research UK/United Kingdom C1287/A12014/Cancer Research UK/United Kingdom C490/A10124/Cancer Research UK/United Kingdom C5047/A10692/Cancer Research UK/United Kingdom C5047/A15007/Cancer Research UK/United Kingdom C5047A8384/Cancer Research UK/United Kingdom C8197/A16565/Cancer Research UK/United Kingdom CA116167/CA/NCI NIH HHS/United States CA116201/CA/NCI NIH HHS/United States CA128978/CA/NCI NIH HHS/United States CA176785/CA/NCI NIH HHS/United States N01 CN25403/CN/NCI NIH HHS/United States P30 CA015083/CA/NCI NIH HHS/United States P30 CA16056/CA/NCI NIH HHS/United States P30 CA68485/CA/NCI NIH HHS/United States P50 CA116201/CA/NCI NIH HHS/United States R01 CA092447/CA/NCI NIH HHS/United States R01 CA77398/CA/NCI NIH HHS/United States R01CA100374/CA/NCI NIH HHS/United States R01CA148667/CA/NCI NIH HHS/United States R01CA64277/CA/NCI NIH HHS/United States R37CA70867/CA/NCI NIH HHS/United States U01 CA116167/CA/NCI NIH HHS/United States U19 CA148065/CA/NCI NIH HHS/United States UM1CA164920/CA/NCI NIH HHS/United States Canadian Institutes of Health Research/Canada Intramural NIH HHS/United States Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. England Human molecular genetics Hum Mol Genet. 2015 May 15;24(10):2966-84. doi: 10.1093/hmg/ddv035. Epub 2015 Feb 4.

PY - 2015

Y1 - 2015

N2 - We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans approximately 14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 x 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-alpha, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

AB - We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans approximately 14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 x 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-alpha, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

U2 - DOI:10.1093/hmg/ddv035

DO - DOI:10.1093/hmg/ddv035

M3 - Article

SN - 0964-6906

VL - 24

SP - 2966

EP - 2984

JO - Hum Mol Genet

JF - Hum Mol Genet

IS - 10

ER -

Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

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