TY - JOUR
T1 - Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
AU - Australian Ovarian Cancer Study Group
AU - The GENICA Network
AU - Orr, Nick
AU - Dudbridge, Frank
AU - Dryden, Nicola
AU - Maguire, Sarah
AU - Novo, Daniela
AU - Perrakis, Eleni
AU - Johnson, Nichola
AU - Ghoussaini, Maya
AU - Hopper, John L.
AU - Southey, Melissa C.
AU - Apicella, Carmel
AU - Stone, Jennifer
AU - Schmidt, Marjanka K.
AU - Broeks, Annegien
AU - Van't Veer, Laura J.
AU - Hogervorst, Frans B.
AU - Fasching, Peter A.
AU - Haeberle, Lothar
AU - Ekici, Arif B.
AU - Beckmann, Matthias W.
AU - Gibson, Lorna
AU - Aitken, Zoe
AU - Warren, Helen
AU - Sawyer, Elinor
AU - Tomlinson, Ian
AU - Kerin, Michael J.
AU - Miller, Nicola
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Schneeweiss, Andreas
AU - Sohn, Chistof
AU - Guénel, Pascal
AU - Truong, Thérèse
AU - Cordina-Duverger, Emilie
AU - Sanchez, Marie
AU - Bojesen, Stig E.
AU - Nordestgaard, Børge G.
AU - Nielsen, Sune F.
AU - Flyger, Henrik
AU - Benitez, Javier
AU - Zamora, Maria Pilar
AU - Perez, Jose Ignacio Arias
AU - Menéndez, Primitiva
AU - Anton-Culver, Hoda
AU - Neuhausen, Susan L.
AU - Brenner, Hermann
AU - Dieffenbach, Aida Karina
AU - Arndt, Volker
AU - Stegmaier, Christa
AU - Hamann, Ute
PY - 2015/5/15
Y1 - 2015/5/15
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 × 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-α, 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 × 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-α, 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.
UR - http://www.scopus.com/inward/record.url?scp=84929498060&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddv035
DO - 10.1093/hmg/ddv035
M3 - Article
C2 - 25652398
AN - SCOPUS:84929498060
SN - 0964-6906
VL - 24
SP - 2966
EP - 2984
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 10
ER -
