Clonal evolution, genomic drivers and effects of therapy in chronic lymphocytic leukemia
Menée sur 156 patients atteints d'une leucémie lymphocytaire chronique, cette étude met en évidence l'effet des traitements sur l'évolution d'anomalies génomiques, notamment d'anomalies du nombre de copies de gènes
Purpose: The identification of gene mutations and structural genomic aberrations that are critically involved in CLL pathogenesis is still evolving. One may postulate that genomic driver lesions with effects on CLL cell proliferation, apoptosis thresholds or chemotherapy resistance should increase in frequency over time when measured sequentially in a CLL cohort. Experimental Design: We sequentially sampled a large well-characterized CLL cohort at a mean of 4 years between samplings and measured acquired copy number aberrations (aCNA) and LOH using SNP 6.0 array profiling and the mutational state of TP53, NOTCH1 and SF3B1 using Sanger sequencing. The paired analysis included 156 patients, of whom 114 remained untreated and 42 received intercurrent therapies, predominantly potent chemo-immunotherapy, during the sampling interval. Results: We identify a strong effect of intercurrent therapies on the frequency of acquisition of aCNAs in CLL. Importantly, the spectrum of acquired genomic changes was largely similar in patients that did or did not receive intercurrent therapies; therefore, various genomic changes that become part of the dominant clones are often already present in CLL cell populations prior to therapy. Further, we provide evidence that therapy of CLL with pre-existing TP53 mutations results in outgrowth of genomically very complex clones which dominate at relapse. Conclusions: Using complementary technologies directed at the detection of genomic events that are present in substantial proportions of the clinically relevant CLL disease bulk, we capture aspects of genomic evolution in CLL over time, including increases in the frequency of genomic complexity, specific recurrent aCNAs and TP53 mutations.