Non-coding recurrent mutations in chronic lymphocytic leukaemia

Xose S. Puente, Silvia Beà, Rafael Valdés-Mas, Neus Villamor, Jesús Gutiérrez-Abril, José I. Martín-Subero, Marta Munar, Carlota Rubio-Pérez, Pedro Jares, Marta Aymerich, Tycho Baumann, Renée Beekman, Laura Belver, Anna Carrio, Giancarlo Castellano, Guillem Clot, Enrique Colado, Dolors Colomer, Dolors Costa, Julio Delgado & 37 others Anna Enjuanes, Xavier P. Estivill, Adolfo A. Ferrando, Josep L. Gelpí, Blanca González, Santiago González, Marcos González, Marta Gut, Jesús M. Hernández-Rivas, Mónica López-Guerra, David Martín-García, Alba Navarro, Pilar Nicolás, Modesto Orozco, Ángel R. Payer, Magda Pinyol, David G. Pisano, Diana A. Puente, Ana C. Queirós, Víctor Quesada, Carlos M. Romeo-Casabona, Cristina Royo, Romina Royo, María Rozman, Nuria Russiñol, Itziar Salaverría, Kostas Stamatopoulos, Hendrik G. Stunnenberg, David Tamborero, María J. Terol, Alfonso Valencia, Nuria López-Bigas, David Torrents, Ivo Gut, Armando López-Guillermo, Carlos López-Otín, Elías Campo

Research output: Contribution to journalArticle

312 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)519-524
Number of pages6
JournalNature
Volume526
Issue number7574
DOIs
Publication statusPublished - 22 Oct 2015
Externally publishedYes

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B-Cell Chronic Lymphocytic Leukemia
Mutation
PAX5 Transcription Factor
Lymphocytosis
Chromosomes
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Puente, X. S., Beà, S., Valdés-Mas, R., Villamor, N., Gutiérrez-Abril, J., Martín-Subero, J. I., ... Campo, E. (2015). Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature, 526(7574), 519-524. https://doi.org/10.1038/nature14666

Non-coding recurrent mutations in chronic lymphocytic leukaemia. / Puente, Xose S.; Beà, Silvia; 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; Carrio, Anna; Castellano, Giancarlo; Clot, Guillem; Colado, Enrique; Colomer, Dolors; Costa, Dolors; Delgado, Julio; Enjuanes, Anna; Estivill, Xavier P.; Ferrando, Adolfo A.; Gelpí, Josep L.; 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; Salaverría, 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; Campo, Elías.

In: Nature, Vol. 526, No. 7574, 22.10.2015, p. 519-524.

Research output: Contribution to journalArticle

Puente, XS, Beà, S, Valdés-Mas, R, Villamor, N, Gutiérrez-Abril, J, Martín-Subero, JI, Munar, M, Rubio-Pérez, C, Jares, P, Aymerich, M, Baumann, T, Beekman, R, Belver, L, Carrio, A, Castellano, G, Clot, G, Colado, E, Colomer, D, Costa, D, Delgado, J, Enjuanes, A, Estivill, XP, Ferrando, AA, Gelpí, JL, González, B, González, S, González, M, Gut, M, Hernández-Rivas, JM, López-Guerra, M, Martín-García, D, Navarro, A, Nicolás, P, Orozco, M, Payer, ÁR, Pinyol, M, Pisano, DG, Puente, DA, Queirós, AC, Quesada, V, Romeo-Casabona, CM, Royo, C, Royo, R, Rozman, M, Russiñol, N, Salaverría, I, Stamatopoulos, K, Stunnenberg, HG, Tamborero, D, Terol, MJ, Valencia, A, López-Bigas, N, Torrents, D, Gut, I, López-Guillermo, A, López-Otín, C & Campo, E 2015, 'Non-coding recurrent mutations in chronic lymphocytic leukaemia', Nature, vol. 526, no. 7574, pp. 519-524. https://doi.org/10.1038/nature14666
Puente XS, Beà S, Valdés-Mas R, Villamor N, Gutiérrez-Abril J, Martín-Subero JI et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015 Oct 22;526(7574):519-524. https://doi.org/10.1038/nature14666
Puente, Xose S. ; Beà, Silvia ; 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 ; Carrio, Anna ; Castellano, Giancarlo ; Clot, Guillem ; Colado, Enrique ; Colomer, Dolors ; Costa, Dolors ; Delgado, Julio ; Enjuanes, Anna ; Estivill, Xavier P. ; Ferrando, Adolfo A. ; Gelpí, Josep L. ; 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 ; Salaverría, 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 ; Campo, Elías. / Non-coding recurrent mutations in chronic lymphocytic leukaemia. In: Nature. 2015 ; Vol. 526, No. 7574. pp. 519-524.
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T1 - Non-coding recurrent mutations in chronic lymphocytic leukaemia

AU - Puente, Xose S.

AU - Beà, Silvia

AU - Valdés-Mas, Rafael

AU - Villamor, Neus

AU - Gutiérrez-Abril, Jesús

AU - Martín-Subero, José I.

AU - Munar, Marta

AU - Rubio-Pérez, Carlota

AU - Jares, Pedro

AU - Aymerich, Marta

AU - Baumann, Tycho

AU - Beekman, Renée

AU - Belver, Laura

AU - Carrio, Anna

AU - Castellano, Giancarlo

AU - Clot, Guillem

AU - Colado, Enrique

AU - Colomer, Dolors

AU - Costa, Dolors

AU - Delgado, Julio

AU - Enjuanes, Anna

AU - Estivill, Xavier P.

AU - Ferrando, Adolfo A.

AU - Gelpí, Josep L.

AU - González, Blanca

AU - González, Santiago

AU - González, Marcos

AU - Gut, Marta

AU - Hernández-Rivas, Jesús M.

AU - López-Guerra, Mónica

AU - Martín-García, David

AU - Navarro, Alba

AU - Nicolás, Pilar

AU - Orozco, Modesto

AU - Payer, Ángel R.

AU - Pinyol, Magda

AU - Pisano, David G.

AU - Puente, Diana A.

AU - Queirós, Ana C.

AU - Quesada, Víctor

AU - Romeo-Casabona, Carlos M.

AU - Royo, Cristina

AU - Royo, Romina

AU - Rozman, María

AU - Russiñol, Nuria

AU - Salaverría, Itziar

AU - Stamatopoulos, Kostas

AU - Stunnenberg, Hendrik G.

AU - Tamborero, David

AU - Terol, María J.

AU - Valencia, Alfonso

AU - López-Bigas, Nuria

AU - Torrents, David

AU - Gut, Ivo

AU - López-Guillermo, Armando

AU - López-Otín, Carlos

AU - Campo, Elías

PY - 2015/10/22

Y1 - 2015/10/22

N2 - 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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