Germline DNA Variations in Breast Cancer Predisposition and Prognosis: A Systematic Review of the Literature

Abstract

Breast cancer is the most common cancer and the second leading cause of death in women worldwide. The disease is caused by a combination of genetic, environmental, lifestyle, and reproductive risk factors. Linkage and family-based studies have identified many pathological germline mutations, which account for around 20% of the genetic risk of familial breast cancer. In recent years, single nucleotide polymorphism-based genetic association studies, especially genome-wide association studies (GWASs), have been very successful in uncovering low-penetrance common variants associated with breast cancer risk. These common variants alone may explain up to an additional 30% of the familial risk of breast cancer. With the advent of available genetic resources and growing collaborations among researchers across the globe, the much needed large sample size to capture variants with small effect sizes and low population frequencies is being addressed, and hence many more common variants are expected to be discovered in the coming days. Here, major GWASs conducted for breast cancer predisposition and prognosis until 2013 are summarized. Few studies investigating other forms of genetic variations contributing to breast cancer predisposition and disease outcomes are also discussed. Finally, the potential utility of the GWAS-identified variants in disease risk models and some future perspectives are presented.

Somatic SNPs of the BRCA2 gene at the fragments encoding RAD51 binding sites of canine mammary tumors

“…Breast cancer is a complex multifactorial disease, which results from an interplay of environmental, reproductive, lifestyle, and genetic risk factors . Canine cancers occur spontaneously, and have similar clinical presentation and pathophysiology to equivalent human cancers.…”

Novel and known genetic variants for male breast cancer risk at 8q24.21, 9p21.3, 11q13.3 and 14q24.1: Results from a multicenter study in Italy

“…To date, a large number of studies have been performed to investigate low-penetrance genetic susceptibility in female BC (FBC), and susceptibility alleles have been reported in about 70 loci widespread in the genome [21]. By contrast, only a few studies addressed the role of low-penetrance alleles in MBC susceptibility [22][23][24].…”

“…21 BC-associated loci widespread in the genome, may influence the risk of BC in men, and whether they may be associated with specific clinical-pathologic characteristics of male BC (MBC).…”

Breast cancer susceptibility: an integrative analysis of genomic data

“…Data from almost 400,000 women affected with breast cancer showed that 281 SNPs are significantly associated with the risk of this disease, which reduced to 233 risk loci when linkage disequilibrium was taken into account. These findings add new information to the already existing recent literature reviews on this subject, which report up to 172 common variants linked to breast cancer susceptibility (3,4,6,(67)(68)(69)(70)(71). These SNPs are estimated to account 15-20% of the genetic component of disease risk (3,72), which clearly implies that much more work is needed to fully elucidate the molecular basis of breast cancer predisposition.…”