Prevalence of pathogenic or likely pathogenic germline mutations in patients with metastatic renal cell cancer.

110 Background: Data from the West suggests that 5-10% of patients with metastatic renal cell cancer (RCC) are known to harbor a pathogenic/likely pathogenic mutation in the RCC-associated genes. However, there are no data from the Indian subcontinent in this regard. Methods: This study was a prospective single-center cohort study conducted at a large tertiary care cancer center in northern India. Patients newly diagnosed with metastatic RCC were eligible to participate and, if willing, were offered pretest counseling and germline genetic testing. We performed whole exome sequencing on blood samples using next-generation sequencing on the Illumina platform. The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined and classified using the ACMG guidelines, and clinical characteristics associated with mutation status were analyzed using a Fisher's exact test. Results: A total of 156 patients with metastatic RCC were enrolled in this study from October 2023 to February 2024. The median age at diagnosis was 44 years, and 67% were men. Histologically, 64% had clear cells, 12% had papillary, and 8% had unknown histology. In RCC-associated genes, 6 patients (3.8%) had P/Lp mutations, of which 4 had mutations in FH and 2 in VHL. Further P/LP variants in the non-RCC genes were detected in 12 additional patients (7.7%), of which 4 were in ATM, 2 in BRIP1, and one each in BRCA1, BARD1, PALB2, MUTYH, MSH6, and PMS2, respectively. The presence of germline P/LP mutation was associated with non-clear histology but not with age and sex. Patients with a P/LP mutation were more likely to have a family history of other cancers (most common, breast cancer) in first and second-degree relatives. Conclusions: 11.5% of patients with metastatic RCC were detected with germline P/LP variants, of which one-third had one of the RCC genes, and the rest had non-RCC gene mutations. Patients with mRCC should have access to germline genetic testing, and the gene panel for patients needs to be expanded to include genes previously classified as non-RCC genes.