Molecular and Immune Landscape of Fumarate Hydratase-mutated Renal Cell Carcinoma

Abstract

Fumarate hydratase-deficient renal cell carcinomas are an aggressive form of kidney cancer that often results in poor prognosis and high fatality rates. The implications of somatic mutations are not well described, and standard treatment has not been established for this renal cell carcinoma subtype. Further molecular characterization of fumarate hydratase-deficient renal cell carcinomas could potentially help to identify biomarkers that can be exploited with future targeted therapies. 2199 renal cell carcinomas were analyzed by DNA sequencing (592-gene panel) and whole- transcriptome sequencing and 40 tumors were identified with pathogenic FH mutations. Co-occurrence of mutation with other cancer-related genes were assessed along with immune profiles and immunotherapy biomarkers. Fumarate hydratase-deficient renal cell carcinomas had a lower prevalence of co-mutation with common renal cell carcinoma driver mutations such as VHL and chromatin remodeling genes when compared to wild type renal cell carcinoma. Conversely, prevalence of several cancer-related genes (MAX, BRCA1, PMS2, BRAF, NF2, and AKT1) was higher in fumarate hydratase-deficient renal cell carcinomas. Immunotherapy biomarkers (mismatch repair deficiency and tumor mutational burden) were detected at low frequency in mutant and wild type renal cell carcinomas, while PDL1 expression occurred at higher frequency in fumarate hydratase-deficient renal cell carcinomas. Fumarate hydratase-mutated kidney tumors may have a different mutational and immune landscape than wild type tumors. The absence of VHL mutations in a significant number of fumarate hydratase deficient renal cell carcinomas suggest that FH mutations may drive tumorigenesis using distinct angiogenic pathways. Our study highlights potential therapeutic implications that will require further study.