Chromophobe renal cell carcinoma (ChRCC)
Features of ChRCC.
Chromophobe renal cell carcinoma (ChRCC) accounts for ~5% of all sporadic renal cancers. ChRCC can occur in two autosomal dominant genetic syndromes: Birt-Hogg-Dube (BHD) syndrome and Tuberous Sclerosis Complex (TSC). They are distinguished from other forms of RCC in part because of their abundant, morphologically-abnormal mitochondria. A fundamental molecular feature of ChRCC is the recurrent pattern of multiple chromosomal losses, including chromosomes 1, 2, 6, 10, 13, and 17. While tremendous progress has been made in more common forms of RCC, including clear cell RCC, there are currently no specific therapies for ChRCC, and the prognosis for metastatic ChRCC is believed to be poorer than for clear cell RCC.
Genetics of ChRCC.
Interestingly, the Cancer Genome Atlas (TCGA0 identified elevated expression of mitochondrial genes and mutations of mitochondrial DNA as characteristic features of ChRCC, and 18% of the tumors carry heteroplasmic mutations in the mitochondrial genes ND1 or ND5, suggesting that metabolic mechanisms may be critical in this disease.
Role of the Henske Lab in ChRCC research.
The goal of our lab is to determine the fundamental metabolic mechanisms contributing to chromophobe-RCC tumorigenesis and to develop a metabolically-targeted therapeutic strategy for individuals with recurrent or metastatic ChRCC, for whom there are currently no proven therapeutic options. Our lab performed the first metabolomic profiling of ChRCC, revealing an unexpected defect in the gamma-glutamyl cycle, with decreased levels of gamma-glutamyl amino acids. This defect is linked to the key enzyme of this pathway, gamma-glutamyl transferase 1 (GGT1), which is expressed at a ~100 fold lower level in ChRCC vs normal kidney in TCGA dataset. These data suggest that a defective glutathione salvage pathway might be “an Achilles’ heel” to ChRCC, leading to sensitization to oxidative stress, mitochondrial damage and programming of glutamine and glucose metabolism.