Long-Term survival of an ovarian cancer patient harboring a RAD51C missense mutation

Meghan R. Sullivan, Rohit Prakash, Yashpal Rawal, Weibin Wang, Patrick Sung, Marc R. Radke, Scott H. Kaufmann, Elizabeth M. Swisher, Kara A. Bernstein, Maria Jasin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbera006083
JournalCold Spring Harbor molecular case studies
Volume7
Issue number2
DOIs
StatePublished - 2021

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

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