A modern view of the role of genetic factors in the etiopathogenesis of breast cancer

Abstract

The aim of this review is to summarize current understandings of the genetic risk factors for the development of breast cancer (BC), evaluate the role of germline mutations and single nucleotide polymorphisms associated with the disease, based on genome-wide association studies (GWAS) and other associative studies. The search for relevant sources was conducted in PubMed, Medline, Cochrane Library, eLIBRARY, and the NHGRI-EBI Catalog of GWAS. The analysis includes works published from January 2007 to December 2022. A total of 197 sources focused on the role of genetic factors in the development of BC were found. Search queries included data on associations of various molecular-genetic markers – germline mutations, and single nucleotide polymorphisms – with the formation of BC. From this body of work, 45 studies were included in the current review. The inclusion criterion for the analysis wasthe presence of GWAS data and associative studies conducted among patients with representative samples with the necessary power. Additionally, results characterizing the clinical-pathological significance (association with molecular subtypes of BC, therapy features, disease prognosis) of BC genetic factors were evaluated. Excluded from the analysis were data from associative studies of candidate genes for malignant breast neoplasms that are morphologically not carcinomas, performed on small (non-representative) patient samples and control groups. Mutations in genes with high and moderate penetrance (BRCA1/2, CHEK2, PALB2, etc.) are associated with the onset of BC in 5 % of cases. Among families with two or more members affected by BC, their share reaches only 30–40 %. GWAS data revealed the role of more than 180 polymorphic loci associated with BC, which determine a heritability rate of about 18 %. According to twin studies, this rate is 1.7 times higher, reaching 31 %. Meanwhile, the contribution of environmental factors is no more than 16 %. The proportion of unidentified hereditary factors in BC formation is about 8 %. However, contemporary studies of associations of various candidate genes (ESR1/2, IGF1, EGFR, VEGF, TNFα, MMPs, etc.), whose signaling pathways regulate BC tumor progression, show their involvement in carcinogenesis. Thus, the unknown heritability in BC formation may reach 40 %. The proportion of germline mutations in major BC predisposition genes in the population is low. Genetic variations within the same gene (e.g., BRCA1) show ethnic or territorial diversity. Nevertheless, a significant portion of BC heritability is determined by various candidate genes, whose role in forming individual BC risk is demonstrated by GWAS. Substantial evidence on the involvement of key carcinogenesis-regulating genes in BC development is being accumulated. Each of the three considered groups of genetic factors has important clinical-pathological significance and can influence the course and prognosis of the disease.