Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
- Memorial Sloan Kettering Cancer Center, United States
- University of Michigan, United States
- Baylor College of Medicine, United States
- University of Washington, United States
- Ludwig-Maximilians University, Germany
- Metabolon Inc, United States
- Cedars-Sinai Medical Center, United States
- Dana-Farber Cancer Institute, United States
- Washington University in St Louis, United States
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.
Data availability
The new data generated in this study is primarily tumor/germline sequencing of primary human tumor specimens, and constitutes human subject data. To protect the privacy of the human subjects, we have included somatic mutation calls in Figure 4 Source Data 1, but have withheld germline information. Source data have been provided for Figures 1-5. Controlled access for TCGA sequencing data (RNA-sequencing and whole exome sequencing of CCPAP tumors) are available via GDC commons data portal (https://gdc.cancer.gov/) by querying the 5 CCPAP sample IDs (BP-4760, BP-4784, BP-4795, DV-5567, BP-4177). Data from the The Cancer Genome Atlas Pan-Cancer Analysis Project related to this studied can be downloaded directly from firebrowse.org at the url http://gdac.broadinstitute.org/runs/stddata__2016_01_28/data/KIPAN/20160128/.
Article and author information
Author details
Abraham Ari Hakimi
Funding
Damon Runyon Cancer Research Foundation (Dale F. Frey Award for Breakthrough Scientists DFS-09-14)
- Costas Lyssiotis
Sidney Kimmel Foundation for Cancer Research (Sidney Kimmel Center for Prostate and Urologic Cancers)
- Abraham Ari Hakimi
American Urological Association (Research Scholar Award)
- Abraham Ari Hakimi
V Foundation for Cancer Research (Junior Scholar Award V2016-009)
- Costas Lyssiotis
Sidney Kimmel Foundation for Cancer Research (Kimmel Scholar Award SKF-16-005)
- Costas Lyssiotis
National Institutes of Health (DK097153)
- Costas Lyssiotis
Charles Woodson Research Fund
- Costas Lyssiotis
the UM Pediatric Brain Tumor Initiative
- Costas Lyssiotis
University of Michigan's Program in Chemical Biology (Graduate Assistance in Areas of National Need (GAANN) award)
- Daniel Kremer
National Cancer Institute (P30 CA008748)
- Jianing Xu
- Ed Reznik
- Gunes Gundem
- Philip Jonsson
- Judy Sarungbam
- Anna Bialik
- Francisco Sanchez-Vega
- Jozefina Casuscelli
- Nikolaus Schultz
- Yiyu Dong
- Paul Russo
- Jonathan A Coleman
- Elli Papaemmanuil
- Ying-Bei Chen
- Victor E Reuter
- Chris Sander
- Satish K Tickoo
- Abraham Ari Hakimi
National Cancer Institute (P30 CA046592)
- Costas Lyssiotis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ralph DeBerardinis, UT Southwestern Medical Center, United States
Ethics
Human subjects: Frozen samples and genomic data were acquired through MSKCC IRB approved tissue protocol 06-107.
Version history
- Received: June 12, 2018
- Accepted: March 22, 2019
- Accepted Manuscript published: March 29, 2019 (version 1)
- Accepted Manuscript updated: April 1, 2019 (version 2)
- Version of Record published: April 11, 2019 (version 3)
Copyright
© 2019, Xu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
eLife 8:e38986.
https://doi.org/10.7554/eLife.38986
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