Homologous Recombination Deficiency: Cancer Predispositions and Treatment Implications

Homologous recombination (HR) is a highly accurate DNA repair mechanism. Several HR genes are established cancer susceptibility genes with clinically actionable pathogenic variants (PVs). Classically, BRCA1 and BRCA2 germline PVs are associated with significant breast and ovarian cancer risks. Patients with BRCA1 or BRCA2 PVs display worse clinical outcomes but respond better to platinum-based chemotherapies and poly-ADP ribose polymerase inhibitors, a trait termed “BRCAness.” With the advent of whole-exome sequencing and multigene panels, PVs in other HR genes are increasingly identified among familial cancers. As such, several genes such as PALB2 are reclassified as cancer predisposition genes. But evidence for cancer risks remains unclear for many others. In this review, we will discuss cancer predispositions and treatment implications beyond BRCA1 and BRCA2, with a focus on 24 HR genes: 53BP1, ATM, ATR, ATRIP, BARD1, BLM, BRIP1, DMC1, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RIF1, RMI1, RMI2, RPA1, TOP3A, TOPBP1, XRCC2, and XRCC3. Implications for Practice: This review provides a comprehensive reference for readers to quickly identify potential cancer predisposing homologous recombination (HR) genes, and to generate research questions for genes with inconclusive evidence. This review also evaluates the “BRCAness” of each HR member. Clinicians can refer to these discussions to identify potential candidates for future clinical trials.