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

Franck Raynaud, Marco Mina, Daniele Tavernari, Giovanni Ciriello, Marcel Kool
2018 PLoS Genetics  
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
more » ... hromosomal 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.
doi:10.1371/journal.pgen.1007669 pmid:30212491 pmcid:PMC6155543 fatcat:de37xjvmxrgerojn7etkgkfhuu