Integrated Molecular Characterization of Fumarate Hydratase-deficient Renal Cell Carcinoma

Abstract

Purpose: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC. Experimental Design: Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathological and follow-up data of these patients were recorded. Results: We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype (CIMP), displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor-suppressors and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrate that patients receiving immune checkpoint blockade-based treatment achieved improved progression free-survival over those treated with antiangiogenic monotherapy (median: 13.3 vs. 5.1 months, P = 0.03). Conclusions: These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.