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

By V. Quesada, Laura Conde, N. Villamor, G. R. Ordóñez, P. Jares, Laia Bassaganyas, A. Ramsay, S. Beá, M. Pinyol, A. Martínez‐Trillos and 31 more. Nature Genetics, 2011

1,154 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5fbe61b94e014668eff875290c9339d154c205aa

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Citations in the corpus

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma (2013, methodology): “D327V) had been previously identified in one IGHV-mutated chronic lymphocytic leukemia (CLL) (18).”
Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy (2015, background): “The underlying mechanism notwithstanding, it is becoming clear that alterations in splicing factors are important drivers of hematologic malignancies, as evidenced by the discovery of acquired mutations in the splicing factor gene SF3B1 in chronic lymphocytic leukemia (37) and myelodysplasia (38).”
Lessons from the cancer genome. (2013, neutral): “In CLL, SF3B1 mutations correlate with more rapid disease progression and lower overall survival (Quesada et al., 2012; Wang et al., 2011a).”
Evolution and impact of subclonal mutations in chronic lymphocytic leukemia (2013, positive): “While intertumoral (Quesada et al., 2012; Wang et al., 2011) and intratumoral (Schuh et al., 2012; Stilgenbauer et al., 2007) genetic heterogeneity had been previously demonstrated in CLL, our use of WES-based algorithms enabled a more comprehensive study of clonal evolution and its clinical impact.”