Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
2019
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
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.
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