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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.<\/jats:p>","DOI":"10.7554\/elife.38986","type":"journal-article","created":{"date-parts":[[2019,3,29]],"date-time":"2019-03-29T09:00:17Z","timestamp":1553850017000},"source":"Crossref","is-referenced-by-count":39,"title":["Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma"],"prefix":"10.7554","volume":"8","author":[{"given":"Jianing","family":"Xu","sequence":"first","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6511-5947","authenticated-orcid":true,"given":"Ed","family":"Reznik","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States"},{"name":"Center 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