Anniversary Lecture

Clinical impact of the genomic/epigenomic perspective in chronic lymphocytic leukemia

Dr. Elías Campo

Chronic lymphocytic leukemia is the most frequent leukemia in Western countries and has a very heterogeneous behavior from very indolent to aggressive clinical evolution. Genomic studies have provided a comprehensive view of somatic mutations and epigenetic changes in chronic lymphocytic leukemia revealing a remarkable molecular heterogeneity with only few genes mutated in up to 10-15% of the patients and a relatively large number of genes recurrently mutated at low frequency. Approximately 60 candidate driver genes have been identified that tend to cluster in different pathways including NOTCH1 signaling, RNA metabolism, BCR signaling, DNA damage response, cell cycle regulation, chromatin modification and NFkB signaling among others. These genetic alterations are differentially distributed in clinical and biological subsets of the disease indicating that they may drive at least in part their heterogeneous evolution. Genome wide methylation analysis has identified three epigenetic subgroups with a distinct distribution of genetic changes, IGHV gene repertoire and stereotyped Bcell receptors. New epigenetic studies are revealing the marked modulation of regulatory regions in CLL compared to normal B cells. The genomic landscape of CLL is highly dynamic in the evolution of the disease. The distribution of mutations in monoclonal B-cell lymphocytosis is similar to those of population-based CLL. However, mutations in TP53, SF3B1, POT1, ATM and RPS15 increase their frequency in progressed disease. Chemotherapy and new target treatments also modulate the landscape of mutations of the disease with the selection of resistant clones. Most CLL have a complex intratumor heterogeneity that influences the evolution of the disease. Copy number alterations tend to be acquired early in the evolution of the disease and remain stable, whereas the mutational heterogeneity increases in the evolution of a subset of tumors Deep target sequencing has detected frequent subclonal mutations in nearly all genes that may even be the sole genetic alteration in approximately 20% of the cases. These small mutated subclones may have a similar prognostic impact as mutations in larger clones. The accumulative number of driver alterations and the subclonal heterogeneity of the disease discriminate patients with differences in clinical behavior. These global genomic and epigenomic studies are revealing the molecular complexity of CLL and provide new perspectives that may be useful to orient clinical interventions and improve the management of these patients.