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The GENICA Network,kConFab Investigators,Norwegian Breast Cancer Study,Glubb, Dylan M.,Maranian, Mel J.,Michailidou, K.,Pooley, Karen A.,Meyer, Kerstin B.,Kar, S.,Carlebur, S.,O'Reilly, M.,Betts, Josh University of Chicago Press [etc.] 2015 American journal of human genetics Vol.96 No.1
Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER<SUP>+</SUP>: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, p<SUB>trend</SUB> = 5.7 x 10<SUP>-44</SUP>) and estrogen-receptor-negative (ER<SUP>-</SUP>: OR = 1.10, 95% CI = 1.05-1.15, p<SUB>trend</SUB> = 3.0 x 10<SUP>-4</SUP>) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [p<SUB>cond</SUB> = 1.61 x 10<SUP>-5</SUP>]) and five variants composing iCHAV3 (lead rs11949391; ER<SUP>+</SUP>: OR = 0.90, 95% CI = 0.87-0.93, p<SUB>cond</SUB> = 1.4 x 10<SUP>-4</SUP>). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2
Ahmed, Shahana,Thomas, Gilles,Ghoussaini, Maya,Healey, Catherine S,Humphreys, Manjeet K,Platte, Radka,Morrison, Jonathan,Maranian, Melanie,Pooley, Karen A,Luben, Robert,Eccles, Diana,Evans, D Gareth,F Nature Publishing Group 2009 Nature genetics Vol.41 No.5
Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08–1.13, P = 4.1 × 10<SUP>−23</SUP>) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92–0.97, P = 1.4 × 10<SUP>−8</SUP>). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.
Michailidou, Kyriaki,Beesley, Jonathan,Lindstrom, Sara,Canisius, Sander,Dennis, Joe,Lush, Michael J,Maranian, Mel J,Bolla, Manjeet K,Wang, Qin,Shah, Mitul,Perkins, Barbara J,Czene, Kamila,Eriksson, Mi Nature Publishing Group, a division of Macmillan P 2015 Nature genetics Vol.47 No.4
Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10<SUP>−8</SUP>. Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
Genome-wide association analysis identifies three new breast cancer susceptibility loci
Ghoussaini, Maya,Fletcher, Olivia,Michailidou, Kyriaki,Turnbull, Clare,Schmidt, Marjanka K,Dicks, Ed,Dennis, Joe,Wang, Qin,Humphreys, Manjeet K,Luccarini, Craig,Baynes, Caroline,Conroy, Don,Maranian, Nature Publishing Group, a division of Macmillan P 2012 Nature genetics Vol.44 No.3
Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ??% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ??0,000 cases and ??8,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 ? 10<SUP>??35</SUP>), 12q24 (rs1292011; P = 4.3 ? 10<SUP>??19</SUP>) and 21q21 (rs2823093; P = 1.1 ? 10<SUP>??12</SUP>). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.