Abstract
BackgroundMutations in the ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHEK2) genes and amplification of the v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene have been suggested to have an important role in breast cancer aetiology. However, whether common variation in these genes has a role in the development of breast cancer or breast cancer survival in humans is still not clear.MethodsWe performed a comprehensive haplotype analysis of the ATM, CHEK2 and ERBB2 genes in a Swedish population-based study, which included 1,579 breast cancer cases and 1,516 controls. We followed the cases for 8.5 years, on average, and retrieved information on the date and cause of death during that period from the nationwide Swedish causes of death registry. We selected seven haplotype-tagging SNPs (tagSNPs) in the ATM gene, six tagSNPs in the CHEK2 gene and seven tagSNPs in the ERBB2 gene that predicted both haplotypic and single locus variations in the respective genes with R2 values ≥ 0.8. These tagSNPs were genotyped in the complete set of cases and controls. We computed expected haplotype dosages of the tagSNP haplotypes and included the dosages as explanatory variables in Cox proportional hazards or logistic regression models.ResultsWe found no association between any genetic variation in the ATM, CHEK2 or ERBB2 genes and breast cancer survival or the risk of developing tumours with certain characteristics.ConclusionOur results indicate that common variants in the ATM, CHEK2 or ERBB2 genes are not involved in modifying breast cancer survival or the risk of tumour-characteristic-defined breast cancer.
Highlights
Twin and family studies consistently indicate that the risk of breast cancer is influenced, in part, by hereditary factors, but high-risk mutations seem to account for only 1–2% of all breast cancer cases in the general population [1]
We found no association between any genetic variation in the ataxia-telangiectasia mutated (ATM), checkpoint kinase 2 (CHEK2) or ERBB2 genes and breast cancer survival or the risk of developing tumours with certain characteristics
Our results indicate that common variants in the ATM, CHEK2 or ERBB2 genes are not involved in modifying breast cancer survival or the risk of tumour-characteristicdefined breast cancer
Summary
Twin and family studies consistently indicate that the risk of breast cancer is influenced, in part, by hereditary factors, but high-risk mutations seem to account for only 1–2% of all breast cancer cases in the general population [1]. We set out to study the role of common variation in key breast cancer candidate genes in relation to breast cancer aetiology, survival and tumour characteristics. The ataxia-telangiectasia mutated (ATM; MIM 607585), checkpoint kinase 2 (CHEK2; MIM 604373) and v-erb-b2. A-T = ataxia-telangiectasia; ATM = ataxia-telangiectasia mutated; CHEK2 = checkpoint kinase 2; CI = confidence interval; dbSNP = Single Nucleotide Polymorphism database; ERBB2 = v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; HWE = Hardy–Weinberg equilibrium; kb = kilobase; LD = linkage disequilibrium; OR = odds ratio; SNP = single nucleotide polymorphism; tagSNP = haplotype-tagging SNP. Avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2; named HER2; MIM 164870) genes have been suggested to have an important role in breast cancer aetiology. Mutations in the ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHEK2) genes and amplification of the v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene have been suggested to have an important role in breast cancer aetiology. Whether common variation in these genes has a role in the development of breast cancer or breast cancer survival in humans is still not clear
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