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  Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

Puente, X. S., Pinyol, M., Quesada, V., Conde, L., Ordonez, G. R., Villamor, N., et al. (2011). Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature, 475(7354), 101-5. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21642962 http://www.nature.com/nature/journal/v475/n7354/pdf/nature10113.pdf.

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Puente, X. S., Author
Pinyol, M., Author
Quesada, V., Author
Conde, L., Author
Ordonez, G. R., Author
Villamor, N., Author
Escaramis, G., Author
Jares, P., Author
Bea, S., Author
Gonzalez-Diaz, M., Author
Bassaganyas, L., Author
Baumann, T., Author
Juan, M., Author
Lopez-Guerra, M., Author
Colomer, D., Author
Tubio, J. M., Author
Lopez, C., Author
Navarro, A., Author
Tornador, C., Author
Aymerich, M., Author
Rozman, M., AuthorHernandez, J. M., AuthorPuente, D. A., AuthorFreije, J. M., AuthorVelasco, G., AuthorGutierrez-Fernandez, A., AuthorCosta, D., AuthorCarrio, A., AuthorGuijarro, S., AuthorEnjuanes, A., AuthorHernandez, L., AuthorYague, J., AuthorNicolas, P., AuthorRomeo-Casabona, C. M., AuthorHimmelbauer, H.1, Author              Castillo, E., AuthorDohm, J. C.1, Author              de Sanjose, S., AuthorPiris, M. A., Authorde Alava, E., AuthorSan Miguel, J., AuthorRoyo, R., AuthorGelpi, J. L., AuthorTorrents, D., AuthorOrozco, M., AuthorPisano, D. G., AuthorValencia, A., AuthorGuigo, R., AuthorBayes, M., AuthorHeath, S., AuthorGut, M., AuthorKlatt, P., AuthorMarshall, J., AuthorRaine, K., AuthorStebbings, L. A., AuthorFutreal, P. A., AuthorStratton, M. R., AuthorCampbell, P. J., AuthorGut, I., AuthorLopez-Guillermo, A., AuthorEstivill, X., AuthorMontserrat, E., AuthorLopez-Otin, C., AuthorCampo, E., Author more..
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1Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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Free keywords: Amino Acid Sequence; Animals; Carrier Proteins/genetics; DNA Mutational Analysis; Genome, Human/*genetics; Humans; Karyopherins/genetics; Leukemia, Lymphocytic, Chronic, B-Cell/*genetics; Molecular Sequence Data; Mutation/*genetics; Myeloid Differentiation Factor 88/chemistry/genetics; Receptor, Notch1/genetics; Receptors, Cytoplasmic and Nuclear/genetics; Reproducibility of Results
 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.

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 Dates: 2011
 Publication Status: Published in print
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Title: Nature
Source Genre: Journal
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Pages: - Volume / Issue: 475 (7354) Sequence Number: - Start / End Page: 101 - 5 Identifier: ISSN: 1476-4687 (Electronic) 0028-0836 (Linking)