Journal Article

Non-coding recurrent mutations in chronic lymphocytic leukaemia

Beà, Silvia, Aymerich, Marta, Baumann, Tycho, Villamor, Neus, Colomer, Dolors, López-Guillermo, Armando, González, Marcos, Estivill, Xavier, Valencia, Alfonso, Gut, Marta, Hernández-Rivas, Jesús M., López-Otín, Carlos, Ferrando, Adolfo A., Royo, Cristina, Valdés-Mas, Rafael, Costa, Dolors, Navarro, Alba, Martín-Subero, José I., Beekman, Renée, Castellano, Giancarlo, Delgado, Julio, Campo, Elías, Colado, Enrique, Stamatopoulos, Kostas, Gelpí, Josep L., Orozco, Modesto, Rozman, María, González, Santiago, Pisano, David G., Quesada, Víctor, Munar, Marta, Jares, Pedro, Romeo-Casabona, Carlos M., Salaverría, Itziar, Rubio-Pérez, Carlota, López-Guerra, Mónica, Queirós, Ana C., Torrents, David, Pinyol, Magda, López-Bigas, Nuria, González, Blanca, Russiñol, Nuria, Puente, Diana A., Belver, Laura, Carrio, Anna, Nicolás, Pilar, Gutiérrez-Abril, Jesús, Tamborero, David, Martín-García, David, Clot, Guillem, Gut, Ivo, Stunnenberg, Hendrik G., Puente, Xose S., Royo, Romina, Terol, María J., Payer, Ángel R., Enjuanes, Anna

2015

Overview

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. Genomic approaches in more than 500 patients are used to extend the number of chronic lymphocytic leukaemia (CLL) driver alterations, and also identify novel recurrent mutations in non-coding regions, including an enhancer of PAX5 and the 3′ untranslated region of NOTCH1 , which lead to aberrant splicing events, increased NOTCH1 protein stability and activity, and an adverse clinical outcome. Driver genes in chronic lymphocytic leukaemia This paper from the International Cancer Genomic Consortium reports the results of a number of genomic approaches used to characterize chronic lymphocytic leukaemia and its precursor in more than 500 patients. As well as extending the number of chronic lymphocytic leukaemia driver alterations found in the coding portion of the genome, the study identies novel recurrent mutations in non-coding regions, including the 3′ UTR of NOTCH1 , which cause aberrant splicing events, an increase in NOTCH1 activity and more aggressive disease, as well as mutations in an enhancer which result in reduced expression of the B-cell-specific transcription factor PAX5.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 3' Untranslated Regions - genetics / 38 / 45 / 45/15 / 45/23 / 45/41 / 45/91 / 631/67 / 82/51 / Alternative Splicing - genetics / B-Lymphocytes - metabolism / Carrier Proteins - genetics / Cell cycle / Chromosomes, Human, Pair 9 - genetics / Chronic lymphocytic leukemia / Diseases / DNA Mutational Analysis / DNA, Neoplasm - genetics / Enhancer Elements, Genetic - genetics / Gene expression / Genetic aspects / Genomes / Genomics / Humanities and Social Sciences / Humans / Immunoglobulins / Leukemia / Leukemia, Lymphocytic, Chronic, B-Cell - genetics / Leukemia, Lymphocytic, Chronic, B-Cell - metabolism / Leukemia, Lymphocytic, Chronic, B-Cell - pathology / Medical prognosis / multidisciplinary / Multivariate analysis / Mutation / Mutation - genetics / Nerve Tissue Proteins - genetics / Nuclear Proteins - genetics / PAX5 Transcription Factor - biosynthesis / PAX5 Transcription Factor - genetics / Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics / Receptor, Notch1 - genetics / Receptor, Notch1 - metabolism / Relapse / Science / Studies / Transcription Factors - genetics / Tumors