Molecular Genetics of Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with marked variability in the clinical course. Some patients survive for decades and never require treatment, whereas other patients may progress rapidly from time of the diagnosis, and some of them die within 2–3 years with refractory disease. Numerous studies have stated that this clinical heterogeneity is a clear reflex of a marked biological diversity. Our understanding of the complexity of the molecular genetics of CLL has broadened profoundly through studies of chromosomal alterations, the immunoglobulin heavy chain gene, genetic lesions identified by whole genome sequencing, deregulated gene expression, micro ribonucleic acid (miRNA) deregulation, epigenome and microenviroment. Expanding knowledge of the molecular genetics of CLL and identification of new molecular markers with potential prognostic and therapeutic significance will have an important future effect on the clinical management of the disease. Key Concepts: Chronic lymphocytic leukaemia is a haematological malignancy with an extremely heterogeneous clinical course. Molecular studies have provided biological evidence underlying the clinical heterogeneity of this disease. The most common recurrent chromosomal abnormalities include deletion 13q, trisomy 12 and deletions 11q, 17p and 6q, and by association of these lesions with the course of the disease, a hierarchical model based on five risk categories was established. One of the most important molecular parameters to define the outcome of CLL patients is the IGHV mutational status. Next-generation sequencing (NGS) techniques have provided a better knowledge of the genetic complexity and heterogeneity of CLL. The integration of the most recurrent and clinically relevant new molecular lesions into the backbone of the FISH hierarchical model has allowed a better understanding of the genetic basis of CLL heterogeneity and led to a significant improvement in patient prognostication. Identification of molecular markers with potential prognostic and therapeutic significance will impact the clinical management of the disease. Keywords: leukaemia; cancer; heterogeneity; prognosis; cytogenetic; mutation