Homologous Recombination Deficiency: Cancer Predispositions and Treatment Implications

Abstract

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.

Keywords: Cancer predisposition; Homologous recombination.

Figure 1

Homologous recombination repair pathway. Ionizing radiation or chemotherapy–induced double‐stranded breaks (DSBs) activate the 53BP1, which stabilizes the chromatin at the DSB site via a 53BP1‐RIF1‐shieldin‐CST complex. This inhibits DNA resection and promotes nonhomologous end joining. BRCA1 competes with 53BP1 for preferential activation of homologous recombination (HR). The DSBs are then sensed by the MRE11‐RAD50‐NBN complex, which loads BLM helicase and EXO1 nuclease onto the double‐stranded DNA (dsDNA) ends to commence 5'‐3' DNA resection. Once the single‐stranded DNA (ssDNA) overhangs are formed, they are coated by RPA, which suppresses further dsDNA resection. ATR then localizes to the ssDNA ends and switches on the ATR‐dependent checkpoint with the aid of ATRIP and TopBP1, arresting the cell cycle for HR to proceed. RAD51 assembles onto the ssDNA, a rate‐limiting step mediated by BRCA1/BARD1, BRCA2/PALB2, and the RAD51 paralogs. The presynaptic filament then undergoes homology search, strand invasion, and DNA synthesis and ligation. Finally, the BTRR complex resolves the Holliday junctions and completes HR.