Timing the origin of genetic therapy resistance in human cancers - analysis results

The emergence of therapy-resistant clones is one of the central challenges in cancer management. Determining whether such clones pre-exist treatment administration or arise de novo in response to it has profound implications for treatment optimisation and patient outcomes. In the manuscript Timing the origin of genetic therapy resistance in human cancers, we introduce TOSCA, a Bayesian R package that integrates longitudinal whole-genome sequencing (WGS) data with clinical records to estimate the timing of genetically driven clonal expansions underlying drug resistance. We validated the framework by recapitulating the known role of aneuploidy in childhood neuroblastoma (see 10.1038/s41588-023-01332-y), and applied it to characterise resistance mechanisms in three clinical cohorts: Acute Myeloid Leukaemia (AML) and Chronic Lymphocytic Leukaemia (CLL): resistance to allogeneic haematopoietic stem cell transplantation; Glioblastoma: resistance to temozolomide, using the public cohort from 10.1016/j.ccell.2019.02.007. We release here the results of our analysis for the four aforementioned cohorts in the form of .rds files, generated using the version of TOSCA available at https://github.com/caravagnalab/tosca. All details necessary for the reproduction of our results are reported in the Methods and Supplementary Materials of the above-mentioned manuscript.