Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2011-07

AUTHORS

Xose S. Puente, Magda Pinyol, Víctor Quesada, Laura Conde, Gonzalo R. Ordóñez, Neus Villamor, Georgia Escaramis, Pedro Jares, Sílvia Beà, 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 Aymerich, María Rozman, Jesús M. Hernández, Diana A. Puente, José M. P. Freije, Gloria Velasco, Ana Gutiérrez-Fernández, Dolors Costa, Anna Carrió, Sara Guijarro, Anna Enjuanes, Lluís Hernández, Jordi Yagüe, Pilar Nicolás, Carlos M. Romeo-Casabona, Heinz Himmelbauer, Ester Castillo, Juliane C. Dohm, Silvia de Sanjosé, Miguel A. Piris, Enrique de Alava, Jesús San Miguel, Romina Royo, Josep L. Gelpí, David Torrents, Modesto Orozco, David G. Pisano, Alfonso Valencia, Roderic Guigó, Mónica Bayés, 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 López-Guillermo, Xavier Estivill, Emili Montserrat, Carlos López-Otín, Elías Campo

ABSTRACT

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. More... »

PAGES

101

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature10113

DOI

http://dx.doi.org/10.1038/nature10113

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1008698030

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21642962


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