Title: Long-term survival of an ovarian cancer patient harboring a RAD51C missense mutation.
Authors: Sullivan, Meghan R; Prakash, Rohit; Rawal, Yashpal; Wang, Weibin; Sung, Patrick; Radke, Marc R; Kaufmann, Scott H; Swisher, Elizabeth M; Bernstein, Kara A; Jasin, Maria
Published In Cold Spring Harb Mol Case Stud, (2021 04)
Abstract: Mutations in homologous recombination (HR) genes predispose to cancer but also sensitize to chemotherapeutics. Although therapy can initially be effective, cancers frequently cease responding, leading to recurrence and poor prognosis. Here we identify a germline mutation in RAD51C, a critical HR factor and known tumor suppressor, in an ovarian cancer patient with exceptionally long, progression-free survival. The RAD51C-T132P mutation is in a highly conserved residue within the nucleotide-binding site and interferes with single-strand DNA binding of the RAD51 paralog complex RAD51B-RAD51C-RAD51D-XRCC2 and association with another RAD51 paralog XRCC3. These biochemical defects lead to highly defective HR and drug sensitivity in tumor cells, ascribing RAD51C-T132P as a deleterious mutation that was likely causal for tumor formation. Conversely, its position within a critical site suggests that it is refractory to secondary mutations that would restore RAD51C gene function and lead to therapy resistance. A need for a greater understanding of the relationship between mutation position and reversion potential of HR genes is underscored, as it may help predict the effectiveness of therapies in patients with HR-deficient cancers.
PubMed ID: 33832919
MeSH Terms: Animals; Binding Sites; Cell Line; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/genetics*; DNA-Binding Proteins/metabolism; Drug Resistance, Neoplasm; Female; Gene Knockout Techniques; Germ-Line Mutation; Humans; Insecta; Mutation, Missense*; Ovarian Neoplasms/genetics*; Rad51 Recombinase/genetics; Recombination, Genetic; Transcriptome