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Xu, Jianing; Reznik, Ed; Lee, Ho-Joon; Gundem, Gunes; Jonsson, Philip; Sarungbam, Judy; Bialik, Anna; Sanchez-Vega, Francisco; Creighton, Chad J.; Hoekstra, Jake; Zhang, Li; Sajjakulnukit, Peter; Kremer, Daniel; Tolstyka, Zachary; Casuscelli, Jozefina; Stirdivant, Steve; Tang, Jie; Schultz, Nikolaus; Jeng, Paul; Dong, Yiyu; Su, Wenjing; Cheng, Emily H.; Russo, Paul; Coleman, Jonathan A.; Papaemmanuil, Elli; Chen, Ying-Bei; Reuter, Victor E.; Sander, Chris; Kennedy, Scott R.; Hsieh, James J.; Lyssiotis, Costas A.; Tickoo, Satish K. and Hakimi, A. Ari (2019): Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma. In: eLife, Vol. 8, e38986 [PDF, 2MB]


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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