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

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

2019

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.

Afficher plus [+]