Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma

Elife. 2019 Apr 1;8:e38986. doi: 10.7554/eLife.38986.

Abstract

While genomic sequencing routinely identifies oncogenic alterations for the majority of cancers, many tumors harbor no discernable driver lesion. Here, we describe the exceptional molecular phenotype of a genomically quiet kidney tumor, clear cell papillary renal cell carcinoma (CCPAP). In spite of a largely wild-type nuclear genome, CCPAP tumors exhibit severe depletion of mitochondrial DNA (mtDNA) and RNA and high levels of oxidative stress, reflecting a shift away from respiratory metabolism. Moreover, CCPAP tumors exhibit a distinct metabolic phenotype uniquely characterized by accumulation of the sugar alcohol sorbitol. Immunohistochemical staining of primary CCPAP tumor specimens recapitulates both the depletion of mtDNA-encoded proteins and a lipid-depleted metabolic phenotype, suggesting that the cytoplasmic clarity in CCPAP is primarily related to the presence of glycogen. These results argue for non-genetic profiling as a tool for the study of cancers of unknown driver.

Keywords: cancer biology; genetics; genomics; human; kidney cancer; metabolomics; mitochondrial DNA; sorbitol.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aerobiosis
  • Carcinoma, Renal Cell / pathology*
  • Cell Respiration*
  • Histocytochemistry
  • Humans
  • Immunohistochemistry
  • Kidney Neoplasms / pathology*
  • Metabolic Networks and Pathways
  • Oxidation-Reduction