Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome.
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ICR Authors
Authors
Zapata, L
Pich, O
Serrano, L
Kondrashov, FA
Ossowski, S
Schaefer, MH
Pich, O
Serrano, L
Kondrashov, FA
Ossowski, S
Schaefer, MH
Document Type
Journal Article
Date
2018-05-31
Date Accepted
2018-04-20
Abstract
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.
Citation
Genome Biology, 2018, 19 (1), pp. 67 -
Source Title
Genome Biology
Publisher
BMC
ISSN
1474-7596
eISSN
1474-760X
1474-760X
1474-760X
Collections
Research Team
Directorate for CEC