University of Sussex
Browse
Hum. Mol. Genet.-2015-Orr-2966-84.pdf (681.34 kB)

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

Download (681.34 kB)
journal contribution
posted on 2023-06-08, 23:10 authored by 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 Guénel, 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 A Perez, P Menéndez, 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 Aittomki, C Blomqvist, S Khan, N Bogdanova, T Dörk, 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 Labrèche, M Dumont, V Kristensen, G G Alnæs, S Nord, A-L Borresen-Dale, W Zheng, S Deming-Halverson, M Shrubsole, J Long, R Winqvist, K Pylkäs, A Jukkola-Vuorinen, M Grip, I L Andrulis, J A Knight, G Glendon, S Tchatchou, P Devilee, R A E M 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 M Van Deurzen, M Kriege, P Hall, J Li, J Liu, K Humphreys, A Cox, S S Cross, Malcolm ReedMalcolm Reed, P D P 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 González-Neira, G Pita, M Rosario Alonso, N Álvarez, 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
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 × 10-25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ~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 × 10-09) and rs13294895 (OR = 1.09 1.06-1.12; P-value = 2.97 × 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 × 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-a, 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. © The Author 2015. Published by Oxford University Press. All rights reserved.

History

Publication status

  • Published

File Version

  • Published version

Journal

Human Molecular Genetics

ISSN

0964-6906

Publisher

Oxford University Press

Issue

10

Volume

24

Page range

2966-2984

Department affiliated with

  • Global Health and Infection Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-03-18

First Open Access (FOA) Date

2016-03-18

First Compliant Deposit (FCD) Date

2016-03-18

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC