Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death

  1. Haley Hieronymus
  2. Rajmohan Murali
  3. Amy Tin
  4. Kamlesh Yadav
  5. Wassim Abida
  6. Henrik Moller
  7. Daniel Berney
  8. Howard Scher
  9. Brett Carver
  10. Peter Scardino
  11. Nikolaus Schultz
  12. Barry Taylor
  13. Andrew Vickers
  14. Jack Cuzick
  15. Charles L Sawyers  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States
  2. Memorial Sloan-Kettering Cancer Center, United States
  3. Icahn School of Medicine at Mount Sinai, United States
  4. Kings College London, United Kingdom
  5. Queen Mary University of London, United Kingdom

Abstract

The level of copy number alteration (CNA), termed CNA burden, in the tumor genome is associated with recurrence of primary prostate cancer. Whether CNA burden is associated with prostate cancer survival or outcomes in other cancers is unknown. We analyzed the CNA landscape of conservatively treated prostate cancer in a biopsy and transurethral resection cohort, reflecting an increasingly common treatment approach. We find that CNA burden is prognostic for cancer-specific death, independent of standard clinical prognostic factors. More broadly, we find CNA burden is significantly associated with disease-free and overall survival in primary breast, endometrial, renal clear cell, thyroid, and colorectal cancer in TCGA cohorts. To assess clinical applicability, we validated these findings in an independent pan-cancer cohort of patients whose tumors were sequenced using a clinically-certified next generation sequencing assay (MSK-IMPACT), where prognostic value varied based on cancer type. This prognostic association was affected by incorporating tumor purity in some cohorts. Overall, CNA burden of primary and metastatic tumors is a prognostic factor, potentially modulated by sample purity and measurable by current clinical sequencing.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files and reference materials. The conservative treatment TAPG copy number cohort array data was deposited in NCBI GEO under accession number GSE103665 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103665, reviewer access token czwruyesnzqbbyn).

The following data sets were generated

Article and author information

Author details

  1. Haley Hieronymus

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

    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:" 0000-0001-6988-4295
  3. Amy Tin

    Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  4. Kamlesh Yadav

    Department of Urology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  5. Wassim Abida

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

    Department of Cancer Epidemiology, Population and Global Health, Kings College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  7. Daniel Berney

    Department of Molecular Oncology, Queen Mary University of London, London, United Kingdom
    Competing interests
    No competing interests declared.
  8. Howard Scher

    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  9. Brett Carver

    Department of Urology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  10. Peter Scardino

    Department of Urology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  11. Nikolaus Schultz

    Marie-Josée and Henry R Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  12. Barry Taylor

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  13. Andrew Vickers

    Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  14. Jack Cuzick

    Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom
    Competing interests
    No competing interests declared.
  15. Charles L Sawyers

    Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States
    For correspondence
    sawyersc@mskcc.org
    Competing interests
    Charles L Sawyers, Senior Editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4955-6475

Funding

Howard Hughes Medical Institute

  • Charles L Sawyers

National Institutes of Health (CA193837)

  • Charles L Sawyers

Prostate Cancer Foundation

  • Kamlesh Yadav

National Institutes of Health (CA092629)

  • Charles L Sawyers

National Institutes of Health (CA155169)

  • Charles L Sawyers

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States

Publication history

  1. Received: April 5, 2018
  2. Accepted: August 13, 2018
  3. Accepted Manuscript published: September 4, 2018 (version 1)
  4. Version of Record published: September 19, 2018 (version 2)
  5. Version of Record updated: September 28, 2018 (version 3)

Copyright

© 2018, Hieronymus 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. Haley Hieronymus
  2. Rajmohan Murali
  3. Amy Tin
  4. Kamlesh Yadav
  5. Wassim Abida
  6. Henrik Moller
  7. Daniel Berney
  8. Howard Scher
  9. Brett Carver
  10. Peter Scardino
  11. Nikolaus Schultz
  12. Barry Taylor
  13. Andrew Vickers
  14. Jack Cuzick
  15. Charles L Sawyers
(2018)
Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death
eLife 7:e37294.
https://doi.org/10.7554/eLife.37294

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    This study’s literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang).