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

Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
Nature Genetics (Impact Factor: 29.65). 12/2011; 44(1):47-52. DOI: 10.1038/ng.1032
Source: PubMed

ABSTRACT 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.

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Available from: Xavier Estivill, Aug 23, 2015
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    • "These two features point towards a possible role for specific antigens in the pathogenesis of CLL. However, and unlike DLBCL, whole genome and exome sequencing analyses have failed to identify genomic aberrations affecting the BCR signalling pathway [Puente et al. 2011; Quesada et al. 2012]. "
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    • "We recently suggested that additional genetic damage such as micro-RNAs disturbances [44e46], mutations in MyD88 [47], NOTCH-1 [48À50] and SF3B1 [51] [52] or trisomy 12 [53] [54], 13 deletion [55], 11q deletion [55] and 17p deletion [55] may be promoted by permanent activation of immunological tolerance mechanisms [33]. Interestingly, transcriptional factors also support that tolerance mechanisms may be implicated in CLL development [33] "
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    • "the other genes was mutated. Our findings are in accordance with the incidences described by others (Puente et al., 2011; Quesada et al., 2011). Thus, there is no correlation between 13q14 rearrangements and any of these mutations. "
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