Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Tumor aneuploidy predicts survival following immunotherapy across multiple cancers

Nature Genetics volume 54, pages 1782–1785 (2022)Cite this article

Subjects

An Author Correction to this article was published on 03 January 2023

This article has been updated

Abstract

Tumor mutational burden (TMB) has emerged as a promising biomarker of immunotherapy response across multiple cancer types; however, clinical outcomes among patients with low TMB tumors are heterogeneous. Herein, we demonstrate that tumor aneuploidy provides independent prognostic value among patients with lower TMB (<80th percentile) tumors treated with immunotherapy. A higher aneuploidy score is associated with poor prognosis following immunotherapy among tumors with low TMB, but not those with high TMB. Importantly, aneuploidy scores can be calculated from existing clinical targeted sequencing infrastructure, facilitating deployment of aneuploidy scores as a clinical biomarker.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Aneuploidy and TMB are synergistic predictors of survival following immunotherapy.
Fig. 2: Defining a clinically applicable threshold of high aneuploidy.

Similar content being viewed by others

Data availability

All data are available from the cBioPortal study found at https://www.cbioportal.org/study/summary?id=tmb_mskcc_2018 and the GENIE v.7.1 release: https://www.synapse.org/#!Synapse:syn7222066/wiki/405659. Aneuploidy scores and FGA values for each sample are provided in the GitHub repository referenced below. Source data are provided with this paper.

Code availability

All code necessary to replicate these analyses are provided in the following GitHub repository: https://github.com/lfspurr/Aneuploidy-ICB16.

Change history

References

  1. Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).

    Article  CAS  Google Scholar 

  2. Strickler, J. H., Hanks, B. A. & Khasraw, M. Tumor mutational burden as a predictor of immunotherapy response: is more always better? Clin. Cancer Res. 27, 1236 (2021).

    Article  CAS  Google Scholar 

  3. Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    Article  CAS  Google Scholar 

  4. Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).

    Article  CAS  Google Scholar 

  5. Fehrenbacher, L. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387, 1837–1846 (2016).

    Article  CAS  Google Scholar 

  6. Romero, D. TMB is linked with prognosis. Nat. Rev. Clin. Oncol. 16, 336–336 (2019).

    Article  Google Scholar 

  7. Rousseau, B. et al. The spectrum of benefit from checkpoint blockade in hypermutated tumors. N. Engl. J. Med. 384, 1168–1170 (2021).

    Article  Google Scholar 

  8. Taylor, A. M. et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 33, 676–689.e3 (2018).

    Article  CAS  Google Scholar 

  9. Lamberti, G. et al. Clinicopathological and genomic correlates of programmed cell death ligand 1 (PD-L1) expression in nonsquamous non-small-cell lung cancer. Ann. Oncol. 31, 807–814 (2020).

    Article  CAS  Google Scholar 

  10. Davoli, T., Uno, H., Wooten, E. C. & Elledge, S. J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 355, eaaf8399 (2017).

    Article  Google Scholar 

  11. Hieronymus, H. et al. Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death. eLife 7, e37294 (2018).

    Article  Google Scholar 

  12. Ben-David, U. & Amon, A. Context is everything: aneuploidy in cancer. Nat. Rev. Genet. 21, 44–62 (2020).

    Article  CAS  Google Scholar 

  13. Spurr, L. F. et al. Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade. Nat. Cancer https://doi.org/10.1038/s43018-022-00467-x (2022).

  14. Spurr, L. F. et al. Quantification of aneuploidy in targeted sequencing data using ASCETS. Bioinformatics 37, 2461–2463 (2020).

    Article  Google Scholar 

  15. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    Article  Google Scholar 

  16. Spurr, L. F. lfspurr/Aneuploidy-ICB: v1.0. Zenodo https://doi.org/10.5281/ZENODO.7181524 (2022).

Download references

Acknowledgements

This work was supported by the Ludwig Cancer Research Foundation (S.P.P. and R.R.W.), a Career Development Award from the LUNGevity Foundation (S.P.P.), an Ullman Scholarship in Translational Cancer Immunology from the University of Chicago Comprehensive Cancer Center (UCCCC) (S.P.P.), a Cancer Spotlight Grant (S.P.P.) from the UCCCC, a Fight Against Cancer Grant from the United-4 A Cure Foundation (S.P.P.) and a National Institutes of Health NCI-SOAR Grant 1R25CA240134-01 (L.F.S.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL, USA

    Liam F. Spurr

  2. Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA

    Liam F. Spurr, Ralph R. Weichselbaum & Sean P. Pitroda

  3. Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA

    Ralph R. Weichselbaum & Sean P. Pitroda

Authors
  1. Liam F. Spurr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ralph R. Weichselbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sean P. Pitroda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the conceptualization, investigation, visualization, writing and editing of this work.

Corresponding author

Correspondence to Sean P. Pitroda.

Ethics declarations

Competing interests

L.F.S. declares no competing interests. R.R.W. reports having stock and other ownership interests with Boost Therapeutics, ImmVira LLC, Reflexion Pharmaceuticals, Coordination Pharmaceuticals Inc., Magi Therapeutics and Oncosenescence; serving in a consulting or advisory role for Aettis Inc., AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., NanoProteagen, NKMax America Inc., Shuttle Pharmaceuticals and Highlight Therapeutics, S.L.; having research grants with Varian and Regeneron; and receiving compensation including travel, accommodations or expense reimbursement from AstraZeneca, Boehringer Ingelheim Ltd. and Merck Serono S.A. S.P.P. has patents outside of the submitted work.

Peer review

Peer review information

Nature Genetics thanks Douglas Johnson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Source data

Source Data Fig. 1

Statistical source data.

Source Data Fig. 2

Statistical source data.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Spurr, L.F., Weichselbaum, R.R. & Pitroda, S.P. Tumor aneuploidy predicts survival following immunotherapy across multiple cancers. Nat Genet 54, 1782–1785 (2022). https://doi.org/10.1038/s41588-022-01235-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41588-022-01235-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer