717 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but aggressive subtype of RCC, and an understanding of their genomic landscape is lacking. Methods: Thirteen FH-deficient RCC and matched normal samples from our medical center were used for whole-exome sequencing and molecular profiling. Transcriptomic sequencing data were analyzed from The Cancer Genome Atlas (TCGA) RCC samples and two independent datasets of FH-mutated RCC. For each patient in our cohort, clinical outcomes were recorded, with median follow-up until March, 2019. Results: We identified FH-deficient RCC had high mutation burden, frequent somatic mutations in MUC4, MUC16, ANKRD6 and PRDM16 and germline pathologic FANCD2 mutation. In contrast to mainly RCC subtypes, FH-deficient RCC exhibited elevated mutational signatures of homologous recombination deficiency (7/13, 53%) and microsatellite instability (4/13, 30%). Moreover, we revealed that FH-deficient RCC was characteristic of an immunogenic tumor type, with high tumor-specific neoantigen burdens, enhanced immune cells infiltration but immunosuppressive microenvironment. In our cohort, 11 patients received systematic treatments; 63% (5/8) responded poorly to antiangiogenic or anti-mammalian target of rapamycin agents, but all (6/6) achieved benefit from immune checkpoint blockade monotherapy or combination with antiangiogenic agents. Conclusions: Our study provides a better understanding of the mutational landscape of FH-deficient RCC, highlighting the potential of immunotherapy for treating this patient populations.
Incidence of succinate dehydrogenase and fumarate hydratase–deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC
