Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATMmutations in chronic lymphocytic leukemia

Genomic studies have revealed the complex clonal heterogeneity of chronic lymphocytic leukemia (CLL). The acquisition and selection of genomic aberrations may be critical to understanding the progression of this disease. In this study, we have extensively characterized the mutational status of TP53, SF3B1, BIRC3, NOTCH1, and ATMin 406 untreated CLL cases by ultra-deep next-generation sequencing, which detected subclonal mutations down to 0.3% allele frequency. Clonal dynamics were examined in longitudinal samples of 48 CLL patients. We identified a high proportion of subclonal mutations, isolated or associated with clonal aberrations. TP53mutations were present in 10.6% of patients (6.4% clonal, 4.2% subclonal), ATMmutations in 11.1% (7.8% clonal, 1.3% subclonal, 2% germ line mutations considered pathogenic), SF3B1mutations in 12.6% (7.4% clonal, 5.2% subclonal), NOTCH1mutations in 21.8% (14.2% clonal, 7.6% subclonal), and BIRC3mutations in 4.2% (2% clonal, 2.2% subclonal). ATMmutations, clonal SF3B1, and both clonal and subclonal NOTCH1mutations predicted for shorter time to first treatment irrespective of the immunoglobulin heavy-chain variable-region gene (IGHV) mutational status. Clonal and subclonal TP53and clonal NOTCH1mutations predicted for shorter overall survival together with the IGHV mutational status. Clonal evolution in longitudinal samples mainly occurred in cases with mutations in the initial samples and was observed not only after chemotherapy but also in untreated patients. These findings suggest that the characterization of the subclonal architecture and its dynamics in the evolution of the disease may be relevant for the management of CLL patients.