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Title: Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2.
Authors: 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,  Guénel P,  Truong T,  Cordina-Duverger E,  Sanchez M,  Bojesen SE,  Nordestgaard BG,  Nielsen SF,  Flyger H,  Benitez J,  Zamora MP,  Arias Perez JI,  Menéndez P,  Anton-Culver H,  Neuhausen SL,  Brenner H,  Dieffenbach AK,  Arndt V,  Stegmaier C,  Hamann U,  Brauch H,  Justenhoven C,  Brüning T,  Ko YD,  The GENICA Network,  Nevanlinna H,  Aittomäki K,  Blomqvist C,  Khan S,  Bogdanova N,  Dörk T,  Lindblom A,  Margolin S,  Mannermaa A,  Kataja V,  Kosma VM,  Hartikainen JM,  Chenevix-Trench G,  Beesley J,  kConFab Investigators,  Australian Ovarian Cancer Study Group,  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,  Labrèche F,  Dumont M,  Kristensen V,  Alnæs GG,  Nord S,  Borresen-Dale AL,  Zheng W,  Deming-Halverson S,  Shrubsole M,  Long J,  Winqvist R,  Pylkäs 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,  González-Neira A,  Pita G,  Alonso MR,  Álvarez 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
Journal: Hum Mol Genet
Date: 2015 Feb 4
Branches: HREB, LTG, OD
PubMed ID: 25652398
PMC ID: not available
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 × 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.