Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
Open Access
- 1 April 2019
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
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.Keywords
Funding Information
- Damon Runyon Cancer Research Foundation (Dale F. Frey Award for Breakthrough Scientists, DFS-09-14)
- V Foundation for Cancer Research (Junior Scholar Award, V2016-009)
- Sidney Kimmel Foundation for Cancer Research (Kimmel Scholar Award, SKF-16-005)
- National Institutes of Health (DK097153)
- Charles Woodson Research Fund
- The UM Pediatric Brain Tumor Initiative
- University of Michigan (Program in Chemical Biology - Graduate Assistance in Areas of National Need (GAANN) award)
- National Cancer Institute (P30 CA008748)
- National Cancer Institute (P30 CA046592)
- Sidney Kimmel Foundation for Cancer Research
- American Urological Association (Research Scholar Award)
This publication has 56 references indexed in Scilit:
- An integrated map of genetic variation from 1,092 human genomesNature, 2012
- The Life History of 21 Breast CancersCell, 2012
- Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel–Lindau gene and hypoxia-inducible factor pathway-related proteinsLaboratory Investigation, 2011
- Allele-specific copy number analysis of tumorsProceedings of the National Academy of Sciences of the United States of America, 2010
- Fast and accurate long-read alignment with Burrows–Wheeler transformBioinformatics, 2010
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Oxidative stress induces degradation of mitochondrial DNANucleic Acids Research, 2009
- Velvet: Algorithms for de novo short read assembly using de Bruijn graphsGenome Research, 2008
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Statistical significance for genomewide studiesProceedings of the National Academy of Sciences of the United States of America, 2003