eLife (Mar 2019)

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

  • Jianing Xu,
  • Ed Reznik,
  • Ho-Joon Lee,
  • Gunes Gundem,
  • Philip Jonsson,
  • Judy Sarungbam,
  • Anna Bialik,
  • Francisco Sanchez-Vega,
  • Chad J Creighton,
  • Jake Hoekstra,
  • Li Zhang,
  • Peter Sajjakulnukit,
  • Daniel Kremer,
  • Zachary Tolstyka,
  • Jozefina Casuscelli,
  • Steve Stirdivant,
  • Jie Tang,
  • Nikolaus Schultz,
  • Paul Jeng,
  • Yiyu Dong,
  • Wenjing Su,
  • Emily H Cheng,
  • Paul Russo,
  • Jonathan A Coleman,
  • Elli Papaemmanuil,
  • Ying-Bei Chen,
  • Victor E Reuter,
  • Chris Sander,
  • Scott R Kennedy,
  • James J Hsieh,
  • Costas A Lyssiotis,
  • Satish K Tickoo,
  • A Ari Hakimi

Journal volume & issue
Vol. 8


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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.