Genomic Profiling Provides Insight into Chromophobe Renal Cell Carcinoma

Chromophobe renal cell carcinoma (ChRCC) is a rare subtype of RCC that is typically indolent but can become aggressive and metastatic and is generally resistant to conventional therapies. Analyzing data collected by The Cancer Genome Atlas on 66 primary ChRCCs, Davis and colleagues found that the majority of ChRCCs show loss of all or most of certain chromosomes, but not recurrent focal copy-number abnormalities. Separation of the samples based on histopathologic categories revealed that “classic” ChRCC cases had this characteristic pattern of chromosomal losses whereas “eosinophilic” ChRCCs had fewer copy-number alterations. Whole-exome sequencing showed that ChRCCs display a lower median rate of somatic mutations than most cancers, including clear-cell RCC (ccRCC). The only significantly mutated genes were TP53 (32% of samples) and PTEN (9%); no other mutations were observed in more than 5% of cases. Whole-genome sequencing indicated that a subset of ChRCCs were characterized by highly localized substitution mutations, or kataegis, and 12% of ChRCCs analyzed harbored rearrangements involving the TERT promoter and increased TERT expression. Comparative analysis of the DNA methylation and gene expression patterns of ChRCC and ccRCC suggested that ChRCC and ccRCC arise from distinct regions of the kidney, with ChRCC likely arising from the distal nephron, and that at least two distinct subsets of ChRCC exist based on differential gene expression. Transcriptome analysis also suggested that ChRCC relies more heavily on the Krebs cycle and electron transport chain than normal kidney tissue or ccRCC, and sequencing of mitochondrial DNA identified 142 somatic mutation events, including the acquisition of nonsilent mutations in protein-coding mitochondrial genes in 20% of sequenced samples. Combined, these analyses illustrate that ChRCC is a distinct disease entity from other types of RCC, with a different site of origin and different genomic and molecular features, and indicate that specialized therapeutic strategies will be needed for this rare tumor subtype.

Davis CF, Ricketts CJ, Wang M, Yang L, Cherniack AD, Shen H, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 2014 Aug 21 [Epub ahead of print].