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Researchers Classify Cancer-Relevant RAD51C Variants

For a paper appearing in PNAS this week, a team from Memorial Sloan Kettering Cancer Center, the University of Pittsburgh, University of Pennsylvania, and other centers characterize cancer-related mutations in the RAD51C tumor suppressor gene that lead to homologous recombination (HR) deficiency. "Mutations in homologous recombination (HR) genes, including BRCA1, BRCA2, and the RAD51 paralog RAD51C, predispose to tumorigenesis and sensitize cancer to DNA-damaging agents and poly(ADP ribose) polymerase [PARP] inhibitors," the researchers explain, noting that prior studies have flagged some 800 RAD51C variants of uncertain significance with potential ties to cancer risk or cancer treatment. When they used functional experiments, biochemical analyses, and structural modeling on more than 50 of these missense mutations, the authors saw signs that HR deficiency, altered RAD51C interactions, and enhanced PARP inhibitor sensitivity tended to occur when VUSs fell at conserved sites and/or in a so-called Walker A motif in the gene. "Ovarian cancer patients with mutations in this cluster had exceptional long-term survival," the authors write. "Our comprehensive analysis of RAD51C missense variants, including structural modeling of RAD51 paralog complexes, provides insight into RAD51C variant classification that should be valuable in assessing other RAD51 paralog variants."