Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.

TitleExome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.
Publication TypeJournal Article
Year of Publication2012
AuthorsQuesada, Víctor, Conde Laura, Villamor Neus, Ordóñez Gonzalo R., Jares Pedro, Bassaganyas Laia, Ramsay Andrew J., Beà Sílvia, Pinyol Magda, Martínez-Trillos Alejandra, López-Guerra Mónica, Colomer Dolors, Navarro Alba, Baumann Tycho, Aymerich Marta, Rozman María, Delgado Julio, Giné Eva, Hernández Jesús M., González-Díaz Marcos, Puente Diana A., Velasco Gloria, Freije José M. P., Tubío José M. C., Royo Romina, Gelpí Josep-Lluis, Orozco Modesto, Pisano David G., Zamora Jorge, Vázquez Miguel, Valencia Alfonso, Himmelbauer Heinz, Bayes Mónica, Heath Simon, Gut Marta, Gut Ivo, Estivill Xavier, López-Guillermo Armando, Puente Xose S., Campo Elías, and López-Otín Carlos
JournalNat Genet
Date Published2012 Jan
KeywordsAmino Acid Sequence, B-Cell, Chronic, Disease Progression, Exome, Humans, Leukemia, Lymphocytic, Mutation, Phosphoproteins, Ribonucleoprotein, Sequence Alignment, U2 Small Nuclear

Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.