Renal cell carcinoma (RCC) is often caused by genetic mutations that disrupt cellular metabolism. In clear cell papillary RCC (CCPAP), driver mutations are absent but mitochondrial changes still result in a unique metabolic profile, according to a new report by Ed Reznik, Costas Lyssiotis, Satish Tickoo, Ari Hakimi and colleagues.

The researchers compared metabolite abundance in CCPAP lesions, adjacent healthy renal tissue and clear cell RCC (ccRCC) lesions, and found that polyol pathway metabolites, including sorbitol and fructose, were elevated in CCPAP, as was the NADH/NAD ratio. By contrast, metabolites involved in upper glycolysis, usually high in ccRCC, were present at normal levels in CCPAP. Similarly to other RCC histologies, high levels of glutathione implied a cellular oxidative stress response in CCPAP tumours.

Malignant cells often downregulate genes linked to oxidative phosphorylation and upregulate hypoxia-related genes, including HIF. This pattern of gene expression was also observed in CCPAP tumours, but normal lactate levels suggested that mitochondria were not reprogrammed to favour glycolysis.

“Unlike related RCC histologies, HIF activation in CCPAP tumours occurs in the absence of inactivation of VHL and TCEB1,” remarks Reznik. In fact, genomic profiling of CCPAP tumours showed that mutational burden was low and that copy number alterations and genomic rearrangements were absent. “The only recurrent genotype in CCPAP was mitochondrial DNA depletion, which might induce sorbitol accumulation by disrupting mitochondrial oxidative phosphorylation,” explains Lyssiotis.

“Mitochondrial dysfunction may be one of the key initiating events in CCPAP,” suggests Tickoo. “Our findings argue for orthogonal profiling of the large cross-section of cancers that lack identifiable driver mutations,” adds Hakimi. “This enhanced profiling might involve metabolomic, epigenomic and proteomic parameters.”