Abstract
Breast cancer has a strong heritable component, with approximately 15% of cases exhibiting a family history of the disease. Mutations in genes such as BRCA1, BRCA2 and TP53 lead to autosomal dominant inherited cancer susceptibility and confer a high lifetime risk of breast cancers. Identification of mutations in these genes through clinical genetic testing enables patients to undergo screening and prevention strategies, some of which provide overall survival benefit. In addition, a number of mutant alleles have been identified in genes such as CHEK2, PALB2, ATM and BRIP1, which often display incomplete penetrance and confer moderate lifetime risks of breast cancer. Studies are underway to determine how to use the identification of mutations in these genes to guide clinical practice. Altogether, however, mutations in high and moderate penetrance genes probably account for approximately 25% of familial breast cancer risk; the remainder may be due to mutations in as yet unidentified genes or lower penetrance variants. Common low penetrance alleles, which have been mainly identified through genome-wide association studies (GWAS), are generally present at 10 to 50% population frequencies and confer less than 1.5-fold increases in breast cancer risk. A number of single nucleotide polymorphisms (SNPs) have been identified and risk associations extensively replicated in populations of European ancestry, the number of which has substantially increased as a result of GWAS performed by the Collaborative Oncological Gene–environment Study consortium. It is now estimated that 28% of familial breast cancer risk is explained by common breast cancer susceptibility loci. In some cases, SNP associations may be specific to different subsets of women with breast cancer, as defined by ethnicity or estrogen receptor status. Although not yet clinically established, it is hoped that identification of common risk variants may eventually allow identification of women at higher risk of breast cancer and enable implementation of breast cancer screening, prevention or treatment strategies that provide clinical benefit.
Highlights
Breast cancer is the most common malignancy in women, excluding nonmelanoma skin cancer, and the second leading cause of cancer death in women following lung cancer [1]
To identify novel Single nucleotide polymorphism (SNP) associated with breast cancer risk, 29,807 SNPs identified by analysis of nine prior genome-wide association studies (GWAS) but not found in prior breast cancer loci were chosen and data collected for 45,290 cases and 41,880 controls [35]
This study provides a model for the necessary future studies of the functional consequences of the extensive list of common low-risk variants that have been identified from GWAS
Summary
Breast cancer is the most common malignancy in women, excluding nonmelanoma skin cancer, and the second leading cause of cancer death in women following lung cancer [1]. In many candidate gene studies, the frequencies of the three genotypes at a given candidate locus are assayed in population-based breast cancer cases and matched controls, and, assuming a dominant genetic model, the relative risk of breast cancer for individuals with the heterozygote or minor allele homozygote genotypes are calculated using the common allele homozygotes as the baseline. Many of these studies yielded either false positive or nonsignificant associations with breast cancer risk, probably because the majority of the early studies were underpowered [22].
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