Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.

TitleWhole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.
Publication TypeJournal Article
Year of Publication2011
AuthorsPuente, Xose S., Pinyol Magda, Quesada Víctor, Conde Laura, Ordóñez Gonzalo R., Villamor Neus, Escaramis Georgia, Jares Pedro, Beà Sílvia, González-Díaz Marcos, Bassaganyas Laia, Baumann Tycho, Juan Manel, López-Guerra Mónica, Colomer Dolors, Tubío José M. C., López Cristina, Navarro Alba, Tornador Cristian, Aymerich Marta, Rozman María, Hernández Jesús M., Puente Diana A., Freije José M. P., Velasco Gloria, Gutiérrez-Fernández Ana, Costa Dolors, Carrió Anna, Guijarro Sara, Enjuanes Anna, Hernández Lluis, Yagüe Jordi, Nicolás Pilar, Romeo-Casabona Carlos M., Himmelbauer Heinz, Castillo Ester, Dohm Juliane C., de Sanjosé Silvia, Piris Miguel A., de Alava Enrique, San Miguel Jesús, Royo Romina, Gelpí Josep-Lluis, Torrents David, Orozco Modesto, Pisano David G., Valencia Alfonso, Guigó Roderic, Bayes Mónica, Heath Simon, Gut Marta, Klatt Peter, Marshall John, Raine Keiran, Stebbings Lucy A., P Futreal Andrew, Stratton Michael R., Campbell Peter J., Gut Ivo, López-Guillermo Armando, Estivill Xavier, Montserrat Emili, López-Otín Carlos, and Campo Elías
Date Published2011 Jul 7
KeywordsAmino Acid Sequence, Animals, B-Cell, Carrier Proteins, Chronic, Cytoplasmic and Nuclear, DNA Mutational Analysis, Genome, Human, Humans, Karyopherins, Leukemia, Lymphocytic, Molecular Sequence Data, Mutation, Myeloid Differentiation Factor 88, Notch1, Receptor, Receptors, Reproducibility of Results

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.