Abstract
Renal cell carcinoma originates from the lining of the proximal convoluted renal tubule and represents the most common type of kidney cancer. Risk factors and comorbidities might be associated to renal cell carcinoma, while a small fraction of 2-3% emerges from patients with predisposing cancer syndromes, typically associated to hereditary mutations in VHL, folliculin, fumarate hydratase or MET genes. Here, we report a case of renal cell carcinoma in patient with concurrent germline mutations in BRCA1 and RAD51 genes. This case displays an unusual high mutational burden and chromosomal aberrations compared to the typical profile of renal cell carcinoma. Mutational analysis on whole genome sequencing revealed an enrichment of the MMR2 mutational signature, which is indicative of impaired DNA repair capacity. Overall, the tumor displayed a profile of unusual high genomic instability which suggests a possible origin from germline predisposing mutations in the DNA repair genes BRCA1 and RAD51. While BRCA1 and RAD51 germline mutations are well-characterised in breast and ovarian cancer, their role in renal cell carcinoma is still largely unexplored. The genomic instability detected in this case of renal cell carcinoma, along with the presence of unusual mutations, might offer support to clinicians for the development of patient-tailored therapies.