Researchers may have uncovered the germline mutational landscape of Chinese patients with ovarian cancer and identified an enriched RAD51D variant in these patients, according to a recent study published by Feng et al in JCO Global Oncology. The findings could serve as a critical reference for ovarian cancer management and a potential therapeutic target in Chinese patients.
Background
Considering the hereditary factors and treatment management of ovarian cancer, genetic testing is often highly recommended for all patients. These tests can help physicians select the most effective drugs or treatments based on the specific mutations a patient may carry. Previous epidemiologic studies have demonstrated that deleterious homologous recombination repair variants may be linked to inherited ovarian diseases, providing valuable guidance for early prevention and tailored treatment in Chinese patients.
Study Methods and Results
In the recent study, the researchers discovered an enriched RAD51D variant among the patients and also identified its functional implications. Among the patients involved in the study, the variant rates of RAD51D ranked third, and all eight patients with the RAD51D pathologic variant had the same RAD51D K91fs variant: c.270_271dup, p.Lys91Ilefs*13.
The researchers further examined the functional implications of the RAD51D variant in this patient population with the goal of determining whether the enriched variant may play a role in the progression or treatment response of ovarian cancer.
Through a series of assays, they revealed that the RAD51D variant had a tumor growth–promoting ability and that reducing the expression of the RAD51D gene led to growth ability reduction in certain cancer cells, chiefly OVCA429 and OVCA433 cell lines. Re-expression of the RAD51D K91fs variant did not bring back the original tumor growth–promoting ability of RAD51D.
Additionally, the patients with the RAD51D K91fs variant showed a satisfactory response to platinum-based therapy and a favorable prognosis. In the OVCA429 and OVCA433 cell lines, re-expression of the RAD51D wild-type and K91fs variants after endogenous RAD51D knockdown revealed that the K91fs variant increased sensitivity to PARP inhibitors such as olaparib and niraparib compared with the wild-type variant.
The genetic testing showed that 31% (n = 116/373) of the patients had at least one deleterious germline variant, and covariants were found in four patients. Those with deleterious homologous recombination repair variants experienced an earlier onset of ovarian cancer, 42.4% of whom were aged under 50 years, compared with 37.0% of those with BRCA mutations and 30.9% with wild-type genes.
Conclusions
The findings highlighted the potential for novel treatment methods in Chinese patients with ovarian cancer.
The researchers hope the results of their study can provide a valuable reference for future genetic studies and lead to new treatment targets by identifying ethnic differences in mutation rates. The discovery of the RAD51D variant and its implications for treatment response could expand the use of targeted therapies, potentially improving outcomes for many patients.
Disclosure: For full disclosures of the study authors, visit ascopubs.org.
