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

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Abstract

Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL)1,2, 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.

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Figure 1: Somatic mutation profiles of 105 CLL exomes.
Figure 2: Structural impact of SF3B1 alterations.
Figure 3: Novel alternative splicing of FOXP1 in CLL cases.
Figure 4: Clinical analysis of SF3B1 in CLL.

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Acknowledgements

We are grateful to P. Klatt for continuous support, E. Montserrat, J. Valcárcel, P. Nicolás and C. Romeo-Casabona for helpful comments, S. Guijarro, S. Martín, C. Capdevila, M. Sánchez and L. Plá for excellent technical assistance, and N. Villahoz and C. Muro for excellent work in the coordination of the CLL Spanish Consortium. We are also very grateful to all the individuals with CLL who participated in this study. This work was funded by the Spanish Ministry of Science and Innovation (MICINN) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII. C.L-O. is an Investigator of the Botín Foundation.

Author information

V.Q., G.R.O., A.J.R., G.V., J.M.P.F. and X.S.P. developed the bioinformatic algorithms and performed the analysis of sequence data. L.C., P.J., M.P., M.L.-G., D.C. and A.N. were responsible for downstream validation analysis and functional studies. L.B., S.B. and J.M.C.T. studied structural variants. D.A.P., H.H., M.B., S.H. and M.G. were responsible for generating libraries, performing exome capture and running sequencers. M.A. prepared and supervised the bioethics requirements. N.V., A.M.-T., T.B., J.D., E.G., A.L.-G. and E.C. performed clinical and biological studies. M.R., M.G.-D., N.V. and J.M.H. reviewed the pathologic data and confirmed the diagnosis. R.R., J.L.G., M.O., D.G.P., J.Z., M.V. and A.V. were in charge of bioinformatics data management. I.G. coordinated the sequencing efforts and performed primary data analysis. V.Q., X.S.P., X.E., A. L.-G., E.C. and C.L.-O. directed the research and wrote the manuscript, which all authors have approved.

Correspondence to Elías Campo or Carlos López-Otín.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–3 and Supplementary Tables 1–3 and 5–16 (PDF 634 kb)

Supplementary Table 4

Somatic mutations in CLL patients (XLSX 193 kb)

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