Breast cancer susceptibility: current knowledge and implications for genetic counselling

Abstract

Breast cancer is the most common malignancy in women in the Western world. Except for the high breast cancer risk in BRCA1 and BRCA2 mutation carriers as well as the risk for breast cancer in certain rare syndromes caused by mutations in TP53, STK11, PTEN, CDH1, NF1 or NBN, familial clustering of breast cancer remains largely unexplained. Despite significant efforts, BRCA3 could not be identified, but several reports have recently been published on genes involved in DNA repair and single nucleotide polymorphisms (SNPs) associated with an increased breast cancer risk. Although candidate gene approaches demonstrated moderately increased breast cancer risks for rare mutations in genes involved in DNA repair (ATM, CHEK2, BRIP1, PALB2 and RAD50), genome-wide association studies identified several SNPs as low-penetrance breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known genes (FGFR2, TOX3, LSP1, MAP3K1, TGFB1, 2q35 and 8q). Some of these low-penetrance breast cancer susceptibility polymorphisms also act as modifier genes in BRCA1/BRCA2 mutation carriers. This review not only outlines the recent key developments and potential clinical benefit for preventive management and therapy but also discusses the current limitations of genetic testing of variants associated with intermediate and low breast cancer risk.

Figure 1

Genotype–phenotype correlation of heterozygous and homozygous/compound heterozygous mutation carriers for breast cancer predisposition genes and low-penetrance breast cancer susceptibility SNPs. Besides BRCA1 and BRCA2, genes are grouped by association with cancer predisposition syndromes (Table 1), rare intermediate penetrance breast cancer susceptibility genes (Tables 2 and 3), and common low-penetrance breast cancer susceptibility single nucleotide polymorphisms (Tables 2 and 3). Genes are listed in alphabetical order in each group.

Figure 2

Association of mean frequency and relative risk of breast cancer susceptibility genes and loci. On the basis of the information in Tables 2 and 3, the association of mean frequency and mean breast cancer-associated relative risk is displayed illustrating the clear differences between rare mutations in genes involved in DNA repair with intermediate penetrance on the one side and common low penetrance single nucleotide polymorphisms on the other.