Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

Xose S. Puente, Magda Pinyol, Victor Quesada, Laura Conde, Gonzalo R. Ordóñez, Neus Villamor, Georgia Escaramis, Pedro Jares, Sílvia Beá, Marcos González-Díaz, Laia Bassaganyas, Tycho Baumann, Manel Juan, Mónica López-Guerra, Dolors Colomer, José M.C. Tubío, Cristina López, Alba Navarro, Cristian Tornador, Marta AymerichMaria Rozman, Jeśs M. Hernández, Diana A. Puente, José M.P. Freije, Gloria Velasco, Ana Gutiérrez-Fernández, Dolors Costa, Anna Carrio, Sara Guijarro, Anna Enjuanes, Lluis Hernndez, Jordi Yage, Pilar Nicols, Carlos M. Romeo-Casabona, Heinz Himmelbauer, Ester Castillo, Juliane C. Dohm, Silvia De Sanjos, Miguel A. Piris, Enrique De Alava, Jesãs San Miguel, Romina Royo, Josep L. Gelpi, David Torrents, Modesto Orozco, David G. Pisano, Alfonso Valencia, Roderic Guigi, Mãnica Bayes, Simon Heath, Marta Gut, Peter Klatt, John Marshall, Keiran Raine, Lucy A. Stebbings, P. Andrew Futreal, Michael R. Stratton, Peter J. Campbell, Ivo Gut, Armando Lopez-Guillermo, Xavier Estivill, Emili Montserrat, Carlos López-Otín, Elías Campo

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Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.

Original languageEnglish
Pages (from-to)101-105
Number of pages5
Issue number7354
Publication statusPublished - 7 Jul 2011


ASJC Scopus subject areas

  • General

Cite this

Puente, X. S., Pinyol, M., Quesada, V., Conde, L., Ordóñez, G. R., Villamor, N., Escaramis, G., Jares, P., Beá, S., González-Díaz, M., Bassaganyas, L., Baumann, T., Juan, M., López-Guerra, M., Colomer, D., Tubío, J. M. C., López, C., Navarro, A., Tornador, C., ... Campo, E. (2011). Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature, 475(7354), 101-105. https://doi.org/10.1038/nature10113