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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Veröffentlicht in:PLoS genetics Jg. 12; H. 12; S. e1006506
Hauptverfasser: Van den Eynden, Jimmy, Basu, Swaraj, Larsson, Erik
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Public Library of Science 01.12.2016
Public Library of Science (PLoS)
Schlagworte:
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
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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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