Reference Detail

Ref Type

Journal Article

PMID

(33832919)

Authors

Sullivan MR, Prakash R, Rawal Y, Wang W, Sung P, Radke MR, Kaufmann SH, Swisher EM, Bernstein KA, Jasin M

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cold Spring Harbor molecular case studies	7	2	2021 Apr		Cold Spring Harb Mol Case Stud

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
RAD51C	T132P	missense	loss of function	RAD51C T132P lies within the Rad51b, Rad51d, and Xrcc3-interacting region of the Rad51c protein (UniProt.org). T132P retains binding to Rad51b, Rad51c, and Xrcc2 but not Xrcc3 in an in vitro assay in one study (PMID: 33832919), but demonstrates reduced interaction with Rad51b, Rad51d, and Xrcc3 in a yeast assay in another study (PMID: 36099300), results in undetectable interaction with DNA in in vitro analyses, reduced homologous recombination activity compared to wild-type Rad51c in cultured cells (PMID: 36099300, PMID: 33832919), fails to rescue survival of Rad51c-null cells, and results in decreased Rad51 foci formation in cell culture (PMID: 33832919).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RAD51C T132P	ovarian cancer	sensitive	Cisplatin + Paclitaxel	Case Reports/Case Series	Actionable	In a clinical case study, treatment with Platinol (cisplatin) plus Taxol (paclitaxel) following surgery resulted in a response with a progression-free survival of at least 10 years in a patient with ovarian cancer harboring RAD51C T132P, and preclinical studies demonstrated cells expressing RAD51C T132P were sensitive to Platinol (cisplatin) in culture (PMID: 33832919).	33832919
RAD51C T132P	Advanced Solid Tumor	sensitive	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Lynparza (olaparib) treatment resulted in decreased survival of cells expressing RAD51C T132P in culture (PMID: 33832919).	33832919