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

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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 , Beckmann , M W , Gibson , L , Aitken , Z , Warren , H , Sawyer , E , Tomlinson , I , Kerin , M J , Miller , N , Burwinkel , B , Marme , F , Schneeweiss , A , Sohn , C , Guenel , P , Truong , T , Cordina-Duverger , E , Sanchez , M , Bojesen , S E , Nordestgaard , B G , Nielsen , S F , Flyger , H , Benitez , J , Zamora , M P , Perez , J I A , Menendez , P , Anton-Culver , H , Neuhausen , S L , Brenner , H , Nevanlinna , H , Aittomaki , K , Blomqvist , C , Khan , S , GENICA Network , kConFab Investigators & Australian Ovarian Canc Study Grp 2015 , ' Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2 ' Human Molecular Genetics , vol. 24 , no. 10 , pp. 2966-2984 . DOI: 10.1093/hmg/ddv035

Title: Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
Author: 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; Perez, Jose Ignacio Arias; Menendez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Nevanlinna, Heli; Aittomaki, Kristiina; Blomqvist, Carl; Khan, Sofia; GENICA Network; kConFab Investigators; Australian Ovarian Canc Study Grp
Contributor: University of Helsinki, Department of Obstetrics and Gynegology
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Department of Oncology
University of Helsinki, Department of Obstetrics and Gynegology
Date: 2015-05-15
Language: eng
Number of pages: 19
Belongs to series: Human Molecular Genetics
ISSN: 0964-6906
URI: http://hdl.handle.net/10138/225120
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 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.
Subject: GENOME-WIDE ASSOCIATION
ESTROGEN-RECEPTOR-ALPHA
CONFER SUSCEPTIBILITY
FUNCTIONAL VARIANTS
COMMON VARIANTS
ANALYSES REVEAL
RISK LOCUS
EXPRESSION
BINDING
FOXA1
3111 Biomedicine
3123 Gynaecology and paediatrics
3122 Cancers
1184 Genetics, developmental biology, physiology
1182 Biochemistry, cell and molecular biology
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