Prevalence of Germline Variants in Advanced Renal Cell Carcinoma in North India.

Abstract

Purpose: Genetic predisposition plays an important role in the pathogenesis of renal cell carcinoma. The prevalence of pathogenic/likely pathogenic (P/LP) in patients with renal cell cancer (RCC) is highly variable, and close to 40% of these can be missed with the current testing guidelines.

Methods: This is a prospective study of all patients with metastatic RCC unselected for high-risk features, registered at our center between September 2023 and August 2024. Baseline clinicopathologic details were collected, and germline whole-exome sequencing was done on blood samples. Our aim was to determine the frequency of germline mutations in an unselected cohort of patients with metastatic RCC. Germline P/LP variants were visualized using cBioPortal, and chi-square and Mann-Whitney U tests were used to identify differences in patients with/without these variants.

Results: Out of 140 participants, P/LP variants in cancer-predisposition genes were detected in 20%, and 4.2% were in RCC-associated genes. Fumarate hydratase was the most common RCC-associated variant (2.8%), while WT1, BRCA1, BRIP1, and ATM (1.4% each) were the commonest non-RCC-associated variants. RCC-associated genes were more frequent in non-clear cell histology (P = .02); there was no difference in cancer predisposition genes on the basis of age, histology, or sex.

Conclusion: Patients with advanced RCC have a high prevalence of germline variants in both RCC-associated and non-RCC cancer-specific genes irrespective of the high-risk genetic features, signifying the importance of a baseline genetic evaluation in all patients with advanced RCC as it has implications for family screening and, in future, selection of therapy.