Journal Article

Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome

Zapata, Luis, Schaefer, Martin H., Serrano, Luis, Pich, Oriol, Kondrashov, Fyodor A., Ossowski, Stephan

2018

Overview

Background Natural selection shapes cancer genomes. Previous studies used signatures of positive selection to identify genes driving malignant transformation. However, the contribution of negative selection against somatic mutations that affect essential tumor functions or specific domains remains a controversial topic. Results Here, we analyze 7546 individual exomes from 26 tumor types from TCGA data to explore the portion of the cancer exome under negative selection. Although we find most of the genes neutrally evolving in a pan-cancer framework, we identify essential cancer genes and immune-exposed protein regions under significant negative selection. Moreover, our simulations suggest that the amount of negative selection is underestimated. We therefore choose an empirical approach to identify genes, functions, and protein regions under negative selection. We find that expression and mutation status of negatively selected genes is indicative of patient survival. Processes that are most strongly conserved are those that play fundamental cellular roles such as protein synthesis, glucose metabolism, and molecular transport. Intriguingly, we observe strong signals of selection in the immunopeptidome and proteins controlling peptide exposition, highlighting the importance of immune surveillance evasion. Additionally, tumor type-specific immune activity correlates with the strength of negative selection on human epitopes. Conclusions In summary, our results show that negative selection is a hallmark of cell essentiality and immune response in cancer. The functional domains identified could be exploited therapeutically, ultimately allowing for the development of novel cancer treatments.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Acids / Animal Genetics and Genomics / Antigens, Neoplasm - immunology / Antitumor activity / Bias / Bioinformatics / Biomedical and Life Sciences / Cancer / Cancer immunology / Cancer-essential genes / Cell cycle / Consortia / Epitopes / Evolutionary Biology / Exome / Genes / Genes, Neoplasm / Genetic transformation / Genome / Genomes / Genomics / glucose / Glucose metabolism / Glucose transport / Human Genetics / Humans / Immune response / Immunosurveillance / Life Sciences / Microbial Genetics and Genomics / monitoring / Mutation / Natural selection / Negative selection / Neoepitopes / neoplasms / Neoplasms - genetics / Neoplasms - immunology / patients / peptides / Peptides - immunology / Plant Genetics and Genomics / Positive selection / Protein biosynthesis / protein synthesis / Protein turnover / Proteins / Selection, Genetic / Tumor evolution