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. 2015 Oct 22;526(7574):519-24.
doi: 10.1038/nature14666. Epub 2015 Jul 22.

Non-coding recurrent mutations in chronic lymphocytic leukaemia

Xose S Puente  1 , Silvia Beà  2 , Rafael Valdés-Mas  1 , Neus Villamor  3 , Jesús Gutiérrez-Abril  1 , José I Martín-Subero  4 , Marta Munar  5 , Carlota Rubio-Pérez  6 , Pedro Jares  7 , Marta Aymerich  3 , Tycho Baumann  8 , Renée Beekman  2 , Laura Belver  9 , Anna Carrio  3 , Giancarlo Castellano  2 , Guillem Clot  2 , Enrique Colado  10 , Dolors Colomer  3 , Dolors Costa  3 , Julio Delgado  8 , Anna Enjuanes  7 , Xavier Estivill  11 , Adolfo A Ferrando  9 , Josep L Gelpí  5 , Blanca González  3 , Santiago González  5 , Marcos González  12 , Marta Gut  13 , Jesús M Hernández-Rivas  12 , Mónica López-Guerra  3 , David Martín-García  2 , Alba Navarro  2 , Pilar Nicolás  14 , Modesto Orozco  5 , Ángel R Payer  10 , Magda Pinyol  7 , David G Pisano  15 , Diana A Puente  1 , Ana C Queirós  4 , Víctor Quesada  1 , Carlos M Romeo-Casabona  14 , Cristina Royo  2 , Romina Royo  5 , María Rozman  3 , Nuria Russiñol  2 , Itziar Salaverría  2 , Kostas Stamatopoulos  16 , Hendrik G Stunnenberg  17 , David Tamborero  6 , María J Terol  18 , Alfonso Valencia  15 , Nuria López-Bigas  6 , David Torrents  5 , Ivo Gut  13 , Armando López-Guillermo  8 , Carlos López-Otín  1 , Elías Campo  3
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Non-coding recurrent mutations in chronic lymphocytic leukaemia

Xose S Puente et al. Nature. .

Abstract

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.

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