Somatic Mutation Patterns in Hemizygous Genomic Regions Unveil Purifying Selection during Tumor Evolution

Identification of cancer driver genes using somatic mutation patterns indicative of positive selection has become a major goal in cancer genomics. However, cancer cells additionally depend on a large number of genes involved in basic cellular processes. While such genes should in theory be subject t...

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Vydáno v:	PLoS genetics Ročník 12; číslo 12; s. e1006506
Hlavní autoři:	Van den Eynden, Jimmy, Basu, Swaraj, Larsson, Erik
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 01.12.2016 Public Library of Science (PLoS)
Témata:	Alleles ates of america Biology Biology and Life Sciences breast-cancer Cancer Carcinogenesis - genetics Carrier Proteins - genetics cells Colleges & universities Evolution Evolution, Molecular expression Funding Genes genetic-variants Genetics & Heredity Genome, Human Genomes Genomics human cancers Humans Investigations landscape Medical Genetics and Genomics Medicine and Health Sciences Medicinsk genetik och genomik missense mutations Mutation Neoplasm Proteins - biosynthesis Neoplasm Proteins - genetics Neoplasms - genetics Neoplasms - pathology ovarian-cancer p12372 Proteins RNA polymerase RNA Polymerase II - genetics Selection, Genetic - genetics Signal Transduction - genetics spliceosome Tumors v108 Values vulnerabilities
ISSN:	1553-7404, 1553-7390, 1553-7404
On-line přístup:	Získat plný text
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Popis
Shrnutí:	Identification of cancer driver genes using somatic mutation patterns indicative of positive selection has become a major goal in cancer genomics. However, cancer cells additionally depend on a large number of genes involved in basic cellular processes. While such genes should in theory be subject to strong purifying (negative) selection against damaging somatic mutations, these patterns have been elusive and purifying selection remains inadequately explored in cancer. Here, we hypothesized that purifying selection should be evident in hemizygous genomic regions, where damaging mutations cannot be compensated for by healthy alleles. Using a 7,781-sample pan-cancer dataset, we first confirmed this in POLR2A, an essential gene where hemizygous deletions are known to confer elevated sensitivity to pharmacological suppression. We next used this principle to identify several genes and pathways that show patterns indicative of purifying selection to avoid deleterious mutations. These include the POLR2A interacting protein INTS10 as well as genes involved in mRNA splicing, nonsense-mediated mRNA decay and other RNA processing pathways. Many of these genes belong to large protein complexes, and strong overlaps were observed with recent functional screens for gene essentiality in human cells. Our analysis supports that purifying selection acts to preserve the remaining function of many hemizygously deleted essential genes in tumors, indicating vulnerabilities that might be exploited by future therapeutic strategies.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceptualization: EL JVdE.Data curation: JVdE.Formal analysis: JVdE SB.Funding acquisition: EL.Investigation: JVdE SB.Methodology: EL JVdE.Project administration: EL.Supervision: EL.Visualization: JVdE.Writing – original draft: JVdE.Writing – review & editing: EL JVdE SB. The authors have declared that no competing interests exist.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1006506