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Elife. 2019 Apr 1;8. pii: e38986. doi: 10.7554/eLife.38986.

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

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
2
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States.
3
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, United States.
4
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
5
Rogel Cancer Center, University of Michigan, Ann Arbor, United States.
6
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States.
7
Human Genome Sequencing Center, Baylor College of Medicine, Houston, United States.
8
Department of Medicine, Baylor College of Medicine, Houston, United States.
9
Department of Pathology, University of Washington, Seattle, United States.
10
Graduate Program in Chemical Biology, University of Michigan, Ann Arbor, United States.
11
Department of Urology, Ludwig-Maximilians University, Munich, Germany.
12
Metabolon Inc, Durham, United States.
13
Genomics Core, Cedars-Sinai Medical Center, Los Angeles, United States.
14
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, United States.
15
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, United States.
16
cBio Center, Dana-Farber Cancer Institute, Boston, United States.
17
Department of Cell Biology, Harvard Medical School, Boston, United States.
18
Department of Medicine, Molecular Oncology, Siteman Cancer Center, Washington University, St. Louis, United States.
19
Department of Internal Medicine, Division of Gastroenterology, Rogel Cancer Center, University of Michigan, Ann Arbor, United States.
#
Contributed equally

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:

cancer biology; genetics; genomics; human; kidney cancer; metabolomics; mitochondrial DNA; sorbitol

Comment in

PMID:
30924768
PMCID:
PMC6459676
DOI:
10.7554/eLife.38986
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

JX, ER, HL, GG, PJ, JS, AB, FS, CC, JH, LZ, PS, DK, ZT, JC, JT, NS, PJ, YD, WS, EC, PR, JC, EP, YC, VR, CS, SK, JH, CL, ST, AH No competing interests declared, SS This author is a former employee of Metabolon, Inc

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