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

TitleAbnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma.
Publication TypeJournal Article
Year of Publication2019
AuthorsXu, J, Reznik, E, Lee, H-J, Gundem, G, Jonsson, P, Sarungbam, J, Bialik, A, Sánchez-Vega, F, Creighton, CJ, Hoekstra, J, Zhang, L, Sajjakulnukit, P, Kremer, D, Tolstyka, Z, Casuscelli, J, Stirdivant, S, Tang, J, Schultz, N, Jeng, P, Dong, Y, Su, W, Cheng, EH, Russo, P, Coleman, JA, Papaemmanuil, E, Chen, Y-B, Reuter, VE, Sander, C, Kennedy, SR, Hsieh, JJ, Lyssiotis, CA, Tickoo, SK, A Hakimi, A
JournalElife
Volume8
Date Published2019 Apr 01
ISSN2050-084X
Abstract

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.

DOI10.7554/eLife.38986
Alternate JournalElife
PubMed ID30924768
PubMed Central IDPMC6459676
Grant ListDale F. Frey Award for Breakthrough Scientists, DFS-09-14 / / Damon Runyon Cancer Research Foundation / United States
Junior Scholar Award, V2016-009 / / V Foundation for Cancer Research /
Kimmel Scholar Award, SKF-16-005 / / Sidney Kimmel Foundation for Cancer Research /
DK097153 / / National Institutes of Health /
Program in Chemical Biology - Graduate Assistance in Areas of National Need (GAANN) award / / University of Michigan /
P30 CA008748 / / National Cancer Institute /
P30 CA046592 / / National Cancer Institute /
Research Scholar Award / / American Urological Association /
Dale F. Frey Award for Breakthrough Scientists DFS-09-14 / / Damon Runyon Cancer Research Foundation / United States
Sidney Kimmel Center for Prostate and Urologic Cancers / / Sidney Kimmel Foundation for Cancer Research /
Junior Scholar Award V2016-009 / / V Foundation for Cancer Research /
Kimmel Scholar Award SKF-16-005 / / Sidney Kimmel Foundation for Cancer Research /
Graduate Assistance in Areas of National Need (GAANN) award / / University of Michigan's Program in Chemical Biology /