Genetic susceptibility to breast cancer

Abstract

Genetic and lifestyle/environmental factors are implicated in the aetiology of breast cancer. This review summarizes the current state of knowledge on rare high penetrance mutations, as well as moderate and low-penetrance genetic variants implicated in breast cancer aetiology. We summarize recent discoveries from large collaborative efforts to combine data from candidate gene studies, and to conduct genome-wide association studies (GWAS), primarily in breast cancers in the general population. These findings are compared with results from collaborative efforts aiming to identify genetic modifiers in BRCA1 and BRCA2 carriers. Breast cancer is a heterogeneous disease, and tumours from BRCA1 and BRCA2 carriers display distinct pathological characteristics when compared with tumours unselected for family history. The relationship between genetic variants and pathological subtypes of breast cancer, and the implication of discoveries of novel genetic variants to risk prediction in BRCA1/2 mutation carriers and in populations unselected for mutation carrier status, are discussed.

Figure 1

Susceptibility loci in ER‐positive and ER‐negative disease in the general population, and in BRCA1 and BRCA2 carriers. Data from published studies of Easton et al. (Easton et al., 2007; Garcia‐Closas et al., 2008); Milne et al. (2009); Zheng et al. (2009b); Thomas et al. (2009); Ahmed et al. (2009); Cox et al. (2007); Stacey et al. (2008) and Antoniou et al. (2008b); Antoniou et al. (2009).

Figure 2

Cumulative risk of breast cancer for BRCA2 mutation carriers and general population by combined FGFR2 and TOX3 genotypes. The combined FGFR2 genotypes at extremes of risk are as follow: FGFR2/TOX3 = GG/CC, or FGFR2/TOX3 = AA/TT. “Average” represents the cumulative breast cancer risk over all possible modifying effects among BRCA2 mutation carriers, or individuals in the general population born after 1950 (Parkin et al., 2002). The minor allele frequencies for the FGFR2 and TOX3 SNPs were assumed to be 0.39 and 0.26 respectively (adapted from Antoniou et al., 2008b).