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

  1. Jianing Xu
  2. Ed Reznik  Is a corresponding author
  3. Ho-Joon Lee
  4. Gunes Gundem
  5. Philip Jonsson
  6. Judy Sarungbam
  7. Anna Bialik
  8. Francisco Sanchez-Vega
  9. Chad J Creighton
  10. Jake G Hoekstra
  11. Li Zhang
  12. Peter Sajjakulnukit
  13. Daniel Kremer
  14. Zachary P Tolstyka
  15. Jozefina Casuscelli
  16. Steve Stirdivant
  17. Jie Tang
  18. Nikolaus Schultz
  19. Paul S Jeng
  20. Yiyu Dong
  21. Wenjing Su
  22. Emily H-Y Cheng
  23. Paul Russo
  24. Jonathan A Coleman
  25. Elli Papaemmanuil
  26. Ying-Bei Chen
  27. Victor E Reuter
  28. Chris Sander
  29. Scott R Kennedy
  30. James J Hsieh
  31. Costas Lyssiotis  Is a corresponding author
  32. Satish K Tickoo  Is a corresponding author
  33. Abraham Ari Hakimi  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States
  2. University of Michigan, United States
  3. Baylor College of Medicine, United States
  4. University of Washington, United States
  5. Ludwig-Maximilians University, Germany
  6. Metabolon Inc, United States
  7. Cedars-Sinai Medical Center, United States
  8. Dana-Farber Cancer Institute, United States
  9. 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

  1. Jianing Xu

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  2. Ed Reznik

    Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    reznike@mskcc.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6511-5947
  3. Ho-Joon Lee

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  4. Gunes Gundem

    Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  5. Philip Jonsson

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  6. Judy Sarungbam

    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  7. Anna Bialik

    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  8. Francisco Sanchez-Vega

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  9. Chad J Creighton

    Department of Medicine, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  10. Jake G Hoekstra

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  11. Li Zhang

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  12. Peter Sajjakulnukit

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  13. Daniel Kremer

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  14. Zachary P Tolstyka

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  15. Jozefina Casuscelli

    Department of Urology, Ludwig-Maximilians University, Munich, Germany
    Competing interests
    No competing interests declared.
  16. Steve Stirdivant

    Metabolon Inc, Durham, United States
    Competing interests
    Steve Stirdivant, This author is a former employee of Metabolon, Inc..
  17. Jie Tang

    Genomics Core, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States
    Competing interests
    No competing interests declared.
  18. Nikolaus Schultz

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  19. Paul S Jeng

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  20. Yiyu Dong

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  21. Wenjing Su

    Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  22. Emily H-Y Cheng

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  23. Paul Russo

    Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  24. Jonathan A Coleman

    Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  25. Elli Papaemmanuil

    Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  26. Ying-Bei Chen

    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5207-3648
  27. Victor E Reuter

    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  28. Chris Sander

    Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  29. Scott R Kennedy

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  30. James J Hsieh

    Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University in St Louis, St Louis, United States
    Competing interests
    No competing interests declared.
  31. Costas Lyssiotis

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    For correspondence
    clyssiot@med.umich.edu
    Competing interests
    No competing interests declared.
  32. Satish K Tickoo

    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    tickoos@mskcc.org
    Competing interests
    No competing interests declared.
  33. Abraham Ari Hakimi

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    hakimia@mskcc.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0930-8824

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.

Ethics

Human subjects: Frozen samples and genomic data were acquired through MSKCC IRB approved tissue protocol 06-107.

Reviewing Editor

  1. Ralph DeBerardinis, UT Southwestern Medical Center, United States

Publication history

  1. Received: June 12, 2018
  2. Accepted: March 22, 2019
  3. Accepted Manuscript published: March 29, 2019 (version 1)
  4. Accepted Manuscript updated: April 1, 2019 (version 2)
  5. 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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  1. Jianing Xu
  2. Ed Reznik
  3. Ho-Joon Lee
  4. Gunes Gundem
  5. Philip Jonsson
  6. Judy Sarungbam
  7. Anna Bialik
  8. Francisco Sanchez-Vega
  9. Chad J Creighton
  10. Jake G Hoekstra
  11. Li Zhang
  12. Peter Sajjakulnukit
  13. Daniel Kremer
  14. Zachary P Tolstyka
  15. Jozefina Casuscelli
  16. Steve Stirdivant
  17. Jie Tang
  18. Nikolaus Schultz
  19. Paul S Jeng
  20. Yiyu Dong
  21. Wenjing Su
  22. Emily H-Y Cheng
  23. Paul Russo
  24. Jonathan A Coleman
  25. Elli Papaemmanuil
  26. Ying-Bei Chen
  27. Victor E Reuter
  28. Chris Sander
  29. Scott R Kennedy
  30. James J Hsieh
  31. Costas Lyssiotis
  32. Satish K Tickoo
  33. Abraham Ari Hakimi
(2019)
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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