Reference Detail

Ref Type

Journal Article

PMID

(38905575)

Authors

Feng Z, Chen S, An N, Xiu Z, Ju X, Chen X, Bi R, Wang J, Zhu S, Wu X, Wen H

Title

Germline Mutational Landscape and Novel Targetable RAD51D Variant in Chinese Patients With Ovarian Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCO global oncology	10		2024 Jun	e2300454	JCO Glob Oncol

URL

Abstract Text

Genetic variants of ovarian cancer (OV) show ethnic differences, but data from the Chinese population are still insufficient. Here, we elucidate the inheritance landscape in Chinese patients with OV and examine the functional implications of a Chinese-enriched RAD51D variant.Between 2015 and 2018, 373 consecutive patients with OV were prospectively enrolled. Variants of BRCA1/2, other homologous recombination repair (HRR) genes, and DNA mismatch repair (MMR) genes were analyzed using next-generation sequencing. An enriched RAD51D variant was identified, and its functional effects were examined using Cell Counting Kit-8, colony formation, transwell migration, and drug sensitivity assays.Overall, 31.1% (116/373) of patients had at least one pathogenic or likely pathogenic germline variant. BRCA1 and BRCA2 accounted for 16.09% and 5.36%, respectively, with one patient having both variants. In addition, 32 (8.58%) patients carried other HRR gene variants, whereas three (0.8%) patients had MMR gene variants. The RAD51D variant ranked third (8/373, 2.1%), and its rate was much higher than that in other populations. Remarkably, all eight patients harbored the RAD51D K91fs variant (c.270_271dup, p.Lys91Ilefs*13) and demonstrated satisfactory platinum response and favorable prognosis. This variant confers enhanced sensitivity to poly (ADP-ribose) polymerase inhibitors in OV cells. However, the effects on platinum sensitivity were inconsistent across different cell lines. Against the background of the TP53 variant, RAD51D K91fs variant showed increased sensitivity to cisplatin.Our study revealed the inheritance landscape of OV and identified an enriched RAD51D variant in Chinese patients with OV. This can serve as an important reference for OV management and a potential therapeutic target.

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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
RAD51D	K91Ifs*13	frameshift	loss of function - predicted	RAD51D K91Ifs13 indicates a shift in the reading frame starting at amino acid 91 and terminating 13 residues downstream causing a premature truncation of the 328 amino acid Rad51d protein (UniProt.org). K91Ifs13 results in similar levels of migration compared to wild-type Rad51d but fails to inhibit cell proliferation and results in increased sensitivity to PARP inhibitors in Rad51d knock-out cells in culture (PMID: 38905575), and therefore, is predicted to lead to a loss of Rad51d protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RAD51D K91Ifs*13	ovarian cancer	sensitive	Niraparib	Preclinical - Cell culture	Actionable	In a preclinical study, Zejula (niraparib) inhibited viability of ovarian cancer cell lines expressing RAD51D K91Ifs*13 in culture (PMID: 38905575).	38905575
RAD51D K91Ifs*13	ovarian cancer	sensitive	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Lynparza (olaparib) inhibited viability of ovarian cancer cell lines expressing RAD51D K91Ifs*13 in culture (PMID: 38905575).	38905575