Growing recognition of the role for rare missense substitutions in breast cancer susceptibility

Abstract

Most cancer susceptibility genes function as tumor suppressors; accordingly, the focus of mutation screening in breast cancer families has been to identify protein-truncating mutations. However, it is now clear that, for some breast cancer susceptibility genes, a significant proportion of the burden of disease comes from rare missense substitutions. Among genes that have been extensively evaluated, BRCA1, BRCA2, PALB2 and BRIP1 stand as examples where the majority of mutations lead to protein truncation;TP53 provides a counter example, where the majority of pathogenic variants are missense substitutions. In ATM and CHEK2, missense substitutions are probably equally or more important in terms of their frequency and attributable risk. Therefore, ongoing efforts to identify new susceptibility genes should not ignore missense variation.

Figure 1. Functional domain organizations of BRCA1, BRCA2, p53, ATM and CHEK2, the homologous recombination pathway proteins known to harbor significant numbers of pathogenic missense substitutions

The protein domain diagrams are based on information from the InterPro protein sequence analysis and classification database [17], the Uniprot Protein Knowledgebase [18], and the NCBI Conserved Domains Database [19] and curated protein multiple sequence alignments available at the Align-GVGD website [20]. Note that the five protein diagrams are each on a different length scale, but that the length of each protein is given at the right side of each diagram. aa: Amino acid.

Figure 2. Core genes in the pathway for DNA double-strand break repair by homologous recombination

Following detection of DNA double-strand breaks, the MRN complex (MRE11A–RAD50–NBN) activates the ATM kinase. ATM in turn phosphorylates downstream effectors including BRCA1, CHEK2 and p53. CHEK2 and p53 activate cell cycle arrest to provide time for DNA damage repair, and p53 also plays a key role in apoptotic signaling. PALB2 interacts with BRCA1 and BRCA2 and is important for the localization of BRCA2 to sites of DNA repair. BARD1 and BRCA1 are structural homologs and heterodimerize through their amino terminal RING domains. Phosphorylated CtIP (RBBP8) and BRIP1 interact with BRCA1s carboxy-terminal BRCT repeats; these BRCA1-containing complexes stimulate homologous recombination repair and inhibit the relatively mutagenic process of double-strand break repair by nonhomologous end joining. The central section of BRCA2 (encoded by exon 11) has eight RAD51 binding sites that play a role in concentrating RAD51 at sites requiring repair by homologous recombination. RAD51 and its paralogs, including RAD51C and XRCC2, then mediate strand invasion during repair by homologous recombination. Solid arrows represent a direct interaction between the proteins indicated. Dotted arrows represent the impact of a proteins activity on the cellular process indicated [–23].