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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 highdoi:10.1371/journal.pgen.1007669 pmid:30212491 pmcid:PMC6155543 fatcat:de37xjvmxrgerojn7etkgkfhuu