To identify and quantify the factors leading to the occurrence of oncogene hotspot mutations, Hoyos and Zappasodi et al. used tp53, a critical transcription factor involved in genome integrity, as a model. Hypothesizing that the determinants were multi-factorial, a “free fitness” model was developed based on mutation rate, normalized tp53 protein concentration, a yeast assay for functional activity, and an immunogenicity score based on binding prediction. The model highlighted the known recurrent mutations and predicted a stronger role for function and weaker role for immune fitness in germline precancerous lesions, suggesting an opportunity for prophylactic immunotherapy.
Contributed by Ed Fritsch
ABSTRACT: Missense driver mutations in cancer are concentrated in a few hotspots(1). Various mechanisms have been proposed to explain this skew, including biased mutational processes(2), phenotypic differences(3-6) and immunoediting of neoantigens(7,8); 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 cancer(1), 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.
Author Info: (1) Computational Oncology, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Swim Across America Laboratory and Ludwig Col
Author Info: (1) Computational Oncology, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Swim Across America Laboratory and Ludwig Collaborative, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. roz4022@med.cornell.edu. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. roz4022@med.cornell.edu. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. roz4022@med.cornell.edu. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA. roz4022@med.cornell.edu. (3) Swim Across America Laboratory and Ludwig Collaborative, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Computational Oncology, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, USA. (6) Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Experimental and Translational Immunology, Health Technology, Technical University of Denmark, Lyngby, Denmark. (11) Experimental and Translational Immunology, Health Technology, Technical University of Denmark, Lyngby, Denmark. (12) Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Computational Oncology, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, NY, USA. (14) Computational Oncology, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (17) Swim Across America Laboratory and Ludwig Collaborative, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (18) Adaptive Biotechnologies, Seattle, WA, USA. (19) Adaptive Biotechnologies, Seattle, WA, USA. (20) Adaptive Biotechnologies, Seattle, WA, USA. (21) Adaptive Biotechnologies, Seattle, WA, USA. (22) Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, USA. (23) Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, National Institutes of Health, Rockville, MD, USA. (24) Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (25) Swim Across America Laboratory and Ludwig Collaborative, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (26) Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (27) Swim Across America Laboratory and Ludwig Collaborative, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. merghout@mskcc.org. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. merghout@mskcc.org. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. merghout@mskcc.org. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. merghout@mskcc.org. (28) Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA. (29) Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (30) Computational Oncology, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. greenbab@mskcc.org. Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, NY, USA. greenbab@mskcc.org.
