Non-coding recurrent mutations in chronic lymphocytic leukaemia.

TitleNon-coding recurrent mutations in chronic lymphocytic leukaemia.
Publication TypeJournal Article
Year of Publication2015
AuthorsPuente, Xose S., Beà Sílvia, Valdés-Mas Rafael, Villamor Neus, Gutiérrez-Abril Jesús, Martín-Subero José I., Munar Marta, Rubio-Pérez Carlota, Jares Pedro, Aymerich Marta, Baumann Tycho, Beekman Renée, Belver Laura, Carrió Anna, Castellano Giancarlo, Clot Guillem, Colado Enrique, Colomer Dolors, Costa Dolors, Delgado Julio, Enjuanes Anna, Estivill Xavier, Ferrando Adolfo A., Gelpí Josep-Lluis, González Blanca, González Santiago, González Marcos, Gut Marta, Hernández-Rivas Jesús M., López-Guerra Mónica, Martín-García David, Navarro Alba, Nicolás Pilar, Orozco Modesto, Payer Ángel R., Pinyol Magda, Pisano David G., Puente Diana A., Queirós Ana C., Quesada Víctor, Romeo-Casabona Carlos M., Royo Cristina, Royo Romina, Rozman María, Russiñol Nuria, Salaverria Itziar, Stamatopoulos Kostas, Stunnenberg Hendrik G., Tamborero David, Terol María J., Valencia Alfonso, López-Bigas Nuria, Torrents David, Gut Ivo, López-Guillermo Armando, López-Otín Carlos, and Campo Elías
Date Published2015 Oct 22
Keywords3’ Untranslated Regions, Alternative Splicing, B-Cell, B-Cell-Specific Activator Protein, B-Lymphocytes, Carrier Proteins, Chromosomes, Chronic, DNA, DNA Mutational Analysis, Enhancer Elements, Genetic, Genomics, Human, Humans, Leukemia, Lymphocytic, Mutation, Neoplasm, Nerve Tissue Proteins, Non-Receptor Type 11, Notch1, Nuclear Proteins, Pair 9, Protein Tyrosine Phosphatase, Receptor, Transcription Factors

Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3’ region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to >=4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.