Fundamental immune–oncogenicity trade-offs define driver mutation fitness

David Hoyos, Roberta Zappasodi (), Isabell Schulze, Zachary Sethna, Kelvin César Andrade, Dean F. Bajorin, Chaitanya Bandlamudi, Margaret K. Callahan, Samuel A. Funt, Sine R. Hadrup, Jeppe S. Holm, Jonathan E. Rosenberg, Sohrab P. Shah, Ignacio Vázquez-García, Britta Weigelt, Michelle Wu, Dmitriy Zamarin, Laura F. Campitelli, Edward J. Osborne, Mark Klinger, Harlan S. Robins, Payal P. Khincha, Sharon A. Savage, Vinod P. Balachandran, Jedd D. Wolchok, Matthew D. Hellmann, Taha Merghoub (), Arnold J. Levine, Marta Łuksza and Benjamin D. Greenbaum ()
Additional contact information
David Hoyos: Memorial Sloan Kettering Cancer Center
Roberta Zappasodi: Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center
Isabell Schulze: Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center
Zachary Sethna: Memorial Sloan Kettering Cancer Center
Kelvin César Andrade: Clinical Genetics Branch, National Cancer Institute, National Institutes of Health
Dean F. Bajorin: Department of Medicine, Weill Cornell Medical College
Chaitanya Bandlamudi: Memorial Sloan Kettering Cancer Center
Margaret K. Callahan: Department of Medicine, Weill Cornell Medical College
Samuel A. Funt: Department of Medicine, Weill Cornell Medical College
Sine R. Hadrup: Technical University of Denmark
Jeppe S. Holm: Technical University of Denmark
Jonathan E. Rosenberg: Department of Medicine, Weill Cornell Medical College
Sohrab P. Shah: Memorial Sloan Kettering Cancer Center
Ignacio Vázquez-García: Memorial Sloan Kettering Cancer Center
Britta Weigelt: Memorial Sloan Kettering Cancer Center
Michelle Wu: Memorial Sloan Kettering Cancer Center
Dmitriy Zamarin: Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center
Laura F. Campitelli: Adaptive Biotechnologies
Edward J. Osborne: Adaptive Biotechnologies
Mark Klinger: Adaptive Biotechnologies
Harlan S. Robins: Adaptive Biotechnologies
Payal P. Khincha: Clinical Genetics Branch, National Cancer Institute, National Institutes of Health
Sharon A. Savage: Clinical Genetics Branch, National Cancer Institute, National Institutes of Health
Vinod P. Balachandran: Department of Medicine, Weill Cornell Medical College
Jedd D. Wolchok: Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center
Matthew D. Hellmann: Department of Medicine, Weill Cornell Medical College
Taha Merghoub: Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center
Arnold J. Levine: Institute for Advanced Study
Marta Łuksza: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Benjamin D. Greenbaum: Memorial Sloan Kettering Cancer Center

Nature, 2022, vol. 606, issue 7912, 172-179

Abstract: Abstract Missense driver mutations in cancer are concentrated in a few hotspots1. Various mechanisms have been proposed to explain this skew, including biased mutational processes2, phenotypic differences3–6 and immunoediting of neoantigens7,8; however, to our knowledge, no existing model weighs the relative contribution of these features to tumour evolution. We propose a unified theoretical ‘free fitness’ framework that parsimoniously integrates multimodal genomic, epigenetic, transcriptomic and proteomic data into a biophysical model of the rate-limiting processes underlying the fitness advantage conferred on cancer cells by driver gene mutations. Focusing on TP53, the most mutated gene in cancer1, we present an inference of mutant p53 concentration and demonstrate that TP53 hotspot mutations optimally solve an evolutionary trade-off between oncogenic potential and neoantigen immunogenicity. Our model anticipates patient survival in The Cancer Genome Atlas and patients with lung cancer treated with immunotherapy as well as the age of tumour onset in germline carriers of TP53 variants. The predicted differential immunogenicity between hotspot mutations was validated experimentally in patients with cancer and in a unique large dataset of healthy individuals. Our data indicate that immune selective pressure on TP53 mutations has a smaller role in non-cancerous lesions than in tumours, suggesting that targeted immunotherapy may offer an early prophylactic opportunity for the former. Determining the relative contribution of immunogenicity and oncogenic function to the selective advantage of hotspot mutations thus has important implications for both precision immunotherapies and our understanding of tumour evolution.

Date: 2022
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-022-04696-z Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:606:y:2022:i:7912:d:10.1038_s41586-022-04696-z

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-04696-z

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().