Pan-cancer inference of intra-tumor heterogeneity reveals associations with different forms of genomic instability.

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State: Public
Version: Final published version
Serval ID
serval:BIB_FD4F973854FC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Pan-cancer inference of intra-tumor heterogeneity reveals associations with different forms of genomic instability.
Journal
PLoS genetics
Author(s)
Raynaud F., Mina M., Tavernari D., Ciriello G.
ISSN
1553-7404 (Electronic)
ISSN-L
1553-7390
Publication state
Published
Issued date
09/2018
Peer-reviewed
Oui
Volume
14
Number
9
Pages
e1007669
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Genomic instability is a major driver of intra-tumor heterogeneity. However, unstable genomes often exhibit different molecular and clinical phenotypes, which are associated with distinct mutational processes. Here, we algorithmically inferred the clonal phylogenies of ~6,000 human tumors from 32 tumor types to explore how intra-tumor heterogeneity depends on different implementations of genomic instability. We found that extremely unstable tumors associated with DNA repair deficiencies or high chromosomal instability are not the most intrinsically heterogeneous. Conversely, intra-tumor heterogeneity is greatest in tumors exhibiting relatively high numbers of both mutations and copy number alterations, a feature often observed in cancers associated with exogenous mutagens. Independently of the type of instability, tumors with high number of clones invariably evolved through branching phylogenies that could be stratified based on the extent of clonal (early) and subclonal (late) instability. Interestingly, tumors with high number of subclonal mutations frequently exhibited chromosomal instability, TP53 mutations, and APOBEC-related mutational signatures. Vice versa, mutations of chromatin remodeling genes often characterized tumors with few subclonal but multiple clonal mutations. Understanding how intra-tumor heterogeneity depends on genomic instability is critical to identify markers predictive of the tumor complexity and envision therapeutic strategies able to exploit this association.
Keywords
APOBEC Deaminases/genetics, Algorithms, Chromatin Assembly and Disassembly, DNA Copy Number Variations, DNA Repair/genetics, Datasets as Topic, Genome, Human/genetics, Genomic Instability, Humans, Models, Genetic, Mutation Rate, Neoplasms/genetics, Phylogeny, Software, Tumor Suppressor Protein p53/genetics
Pubmed
Web of science
Open Access
Yes
Create date
19/09/2018 10:21
Last modification date
20/08/2019 17:28
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