title: Genetic and epigenetic basis of chronic lymphocytic leukemia.
abstract: OBJECTIVE
  Next-generation sequencing of whole genomes, exomes and DNA methylomes in chronic lymphocytic leukemia (CLL) has provided the first comprehensive view of somatic mutations and methylation changes in this disease. This review summarizes the recent findings in this field and their impact on our current understanding of this neoplasm.
  
  
  RESULTS
  Genomic studies have revealed a remarkable molecular heterogeneity of the disease, 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. The mutated genes tend to cluster in different pathways that include NOTCH1 signaling, RNA splicing, processing and transport machinery, innate inflammatory response, and DNA damage and cell cycle control, among others. NOTCH1 and SF3B1 mutations are emerging as new drivers of aggressive forms of the disease. Genome-wide methylation studies have shown that CLL transformation is associated with a massive hypomethylation phenomenon frequently affecting the enhancer regions. This epigenetic reprogramming maintains an imprint of the putative cell of origin from naïve and memory B-cells.
  
  
  CONCLUSIONS
  Genomic and epigenomic studies of CLL are reshaping our understanding of the disease and provide new perspective for a more individualized diagnosis and new potential therapeutic targets.
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clinic, Universidad de Barcelona, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D057890:Epigenomics; D055106:Genome-Wide Association Study; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D009154:Mutation