Format

Send to

Choose Destination
Genome Biol. 2018 May 31;19(1):67. doi: 10.1186/s13059-018-1434-0.

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

Author information

1
Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003, Barcelona, Spain.
2
Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
3
Evolutionary Genomics Group, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003, Barcelona, Spain.
4
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028, Barcelona, Spain.
5
Design of Biological Systems Group, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003, Barcelona, Spain.
6
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
7
Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluis Companys 23, 08010, Barcelona, Spain.
8
IST Austria (Institute of Science and Technology Austria), Am Campus 1, 3400, Klosterneuburg, Austria.
9
Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003, Barcelona, Spain. stephan.ossowski@med.uni-tuebingen.de.
10
Universitat Pompeu Fabra (UPF), Barcelona, Spain. stephan.ossowski@med.uni-tuebingen.de.
11
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. stephan.ossowski@med.uni-tuebingen.de.
12
Design of Biological Systems Group, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003, Barcelona, Spain. martin.schaefer@crg.eu.

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.

KEYWORDS:

Cancer immunology; Cancer-essential genes; Negative selection; Neoepitopes; Tumor evolution

PMID:
29855388
PMCID:
PMC5984361
DOI:
10.1186/s13059-018-1434-0
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center