Project description:<p>Large-scale whole-exome sequencing (WES) of primary tumor samples enables the unbiased discovery of recurrent putative driver events and patterns of clonal evolution. We report the identification of 44 recurrently mutated genes and 11 recurrent CNVs through the WES of 538 chronic lymphocytic leukemia (CLL) and matched germline DNAs. These include previously unrecognized cancer drivers (e.g., RPS15, IKZF3), and collectively identify nuclear export, MYC activity and MAPK signaling as central pathways affected by somatic mutation in CLL. A clonality analysis of this large dataset further enabled the reconstruction of temporal relationships between these driver events. Several drivers were associated with shorter progression-free survival (PFS) in 280 samples that were collected prior to uniform treatment with front line chemo-immunotherapy, with mature follow up of greater than 10 years. Direct comparison between matched pretreatment and relapse CLL from 59 samples demonstrated marked clonal evolution occurring in more than 95% of these patients. Distinct patterns of clonal evolution in relationship to specific gene alteration were observed, suggesting a hierarchy of fitness amongst mutations. Thus, large WES datasets of clinically informative samples enables the discovery of novel driver genes as well as the network of relationships between the drivers and their impact on disease relapse and clinical outcome.</p>
Project description:THis is a simple ordinary differential equation model describing chemoimmunotherapy of chronic lymphocytic leukemia, including descriptions of the combinatorial effects of chemotherapy and adoptive cellular immunotherapy.
Project description:Clonal and subclonal evolution is involved in the progression of chronic lymphocytic leukemia (CLL). Evolution can work to select not only genetic mutations, but also epigenetic states. Here we performed a long-term longitudinal DNA methylation profiling study of CLL patients to look for associations of epigenetic evolution to different disease courses. In line with the genetic data, large-scale methylation evolution was not present in any of the evaluated long-term untreated (n = 3) and relapsed (n = 2) patients displaying clonal changes of linear type while 3 of the 5 examined refractory patients featured profound changes in DNA methylation.
