Hereditary breast and ovarian cancer: new genes in confined pathways

Key Points Genetic abnormalities in BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of HBOC cases can be ascribed to BRCA1 and BRCA2 mutations. Next-generation sequencing approaches are uncovering novel HBOC factors among affected families without BRCA1 or BRCA2 mutations; at present more than 25 have emerged. New factors generally function in the same genome maintenance pathways as established HBOC factors, indicating substantial locus heterogeneity. Disabled pathways in HBOC are homologous recombination repair (HRR), protection of stalling DNA replication forks, mismatch repair, and cell cycle checkpoint and DNA damage checkpoint control pathways. The new pathogenic variants are rare, which poses challenges to the estimation of risk attribution through patient cohorts. There is a risk that patients or healthy carriers exhibiting pathogenic variants in rare HBOC genes may be excluded from the best possible treatment or presymptomatic screening programmes. Structural and functional analysis can support variant classification in the context of international collaboration and standardized guidelines. Functional approaches are aided by extensive locus heterogeneity, which converges on a relatively small number of genome maintenance pathways that may be reconciled in vitro . This Review summarizes our current understanding of the functions of established and emerging hereditary breast and ovarian cancer genes in genome maintenance pathways. The authors discuss how classifying variants as pathogenic by structural and functional analysis will aid clinical management. Genetic abnormalities in the DNA repair genes BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of cases of HBOC can be ascribed to BRCA1 and BRCA2 mutations. Recently, exome sequencing has uncovered substantial locus heterogeneity among affected families without BRCA1 or BRCA2 mutations. The new pathogenic variants are rare, posing challenges to estimation of risk attribution through patient cohorts. In this Review article, we examine HBOC genes, focusing on their role in genome maintenance, the possibilities for functional testing of putative causal variants and the clinical application of new HBOC genes in cancer risk management and treatment decision-making.