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Fine-Scale mapping of the 11q13 breast cancer susceptibility locus

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Ahmed, S 
Michailidou, K 
Gregory, K 
Dicks, E 


The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799–121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000–120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Perallelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08–1.13, P = 1.49 x 10−21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P 8.41 x 10−5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.



31 Biological Sciences, 32 Biomedical and Clinical Sciences, 3105 Genetics, 4202 Epidemiology, 4203 Health Services and Systems, 42 Health Sciences, 3211 Oncology and Carcinogenesis, Cancer Genomics, Genetics, Breast Cancer, Human Genome, Cancer, Women's Health, 2.1 Biological and endogenous factors, 2 Aetiology, Cancer, Alleles, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 1, Computational Biology, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Linkage Disequilibrium, Neoplasm Grading, Polymorphism, Single Nucleotide, Population Surveillance, Quantitative Trait Loci, Risk Assessment

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Public Library of Science (PLoS)
Cancer Research UK (Grant IDs: C1287/A10118, C1287/A12014, C490/A10124, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), European Community's Seventh Framework Programme (Grant ID: HEALTH-F2-2009-223175), National Institutes of Health (Grant IDs: CA128978, CA116167, CA176785, CA116201, CA63464, CA54281, CA098758, CA132839, R01CA100374, R01CA64277, R01CA148667, R37CA70867, R01CA092447), National Institute for Health Research. See also Table K via