Clinical implications of the molecular genetics of chronic lymphocytic leukemia

Abstract

Genetics and molecular genetics have contributed to clarify the biological bases of the clinical heterogeneity of chronic lymphocytic leukemia. In recent years, our knowledge of the molecular genetics of chronic lymphocytic leukemia has significantly broadened, offering potential new clinical implications. Mutations of TP53 and ATM add prognostic information independently of fluorescence in situ hybridization cytogenetic stratification. In addition, next generation sequencing technologies have allowed previously unknown genomic alterations in chronic lymphocytic leukemia to be identified. Mutations of NOTCH1, SF3B1 and BIRC3 have been associated with short time to progression and survival. Each of these lesions recognizes a different distribution across different clinical phases and biological subgroups of the disease. The clinical implications of these molecular lesions are in some instances well established, such as in the case of patients with TP53 disruption, who should be considered for alternative therapies/allogeneic stem cell transplant upfront, or in patients with ATM disruption, who are candidates to rituximab-based immunochemotherapy. On the contrary, NOTCH1, SF3B1 and BIRC3 mutations appear to have a specific significance, the clinical value of which is currently being validated, i.e. association to Richter syndrome transformation for NOTCH1 mutations, and short progression-free survival after treatment for SF3B1 mutations. Certainly, these new lesions have helped clarify the molecular bases of chronic lymphocytic leukemia aggressiveness beside TP53 disruption. This review covers the recent advancements in our understanding of the molecular genetics of chronic lymphocytic leukemia and discusses how they are going to translate into clinical implications for patient management.

Figure 1.

NOTCH1, SF3B1, BIRC3, TP53 mutation type and distribution in CLL. Schematic representation of the human NOTCH1 (A), SF3B1 (B), BIRC3 (C), and TP53 (D) proteins, with their key functional domains. Color-coded symbols indicate the type and position of the mutations. Mutations are from the Novara CLL mutation database and from the COSMIC database (v. 61).

Figure 2.

Expected survival of CLL patients stratified according to the integrated mutational and cytogenetic model and compared to the matched general population. Expected survival is calculated at ten years.