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

被引：784

作者：

Quesada, Victor ^{[1
]}

Conde, Laura ^{[2
]}

Villamor, Neus ^{[2
]}

Ordonez, Gonzalo R. ^{[1
]}

Jares, Pedro ^{[2
]}

Bassaganyas, Laia ^{[3
]}

Ramsay, Andrew J. ^{[1
]}

Bea, Silvia ^{[2
]}

Pinyol, Magda ^{[4
]}

Martinez-Trillos, Alejandra

Lopez-Guerra, Monica ^{[2
]}

Colomer, Dolors ^{[2
]}

Navarro, Alba ^{[2
]}

Baumann, Tycho ^{[5
]}

Aymerich, Marta ^{[2
]}

Rozman, Maria ^{[2
]}

Delgado, Julio ^{[5
]}

Gine, Eva ^{[5
]}

Hernandez, Jesus M. ^{[6
]}

Gonzalez-Diaz, Marcos ^{[6
]}

Puente, Diana A. ^{[1
]}

Velasco, Gloria ^{[1
]}

Freije, Jose M. P. ^{[1
]}

Tubio, Jose M. C. ^{[3
]}

Royo, Romina ^{[7
]}

Gelpi, Josep L. ^{[7
]}

Orozco, Modesto ^{[7
]}

Pisano, David G. ^{[8
]}

Zamora, Jorge ^{[8
]}

Vazquez, Miguel ^{[8
]}

Valencia, Alfonso ^{[8
]}

Himmelbauer, Heinz ^{[9
]}

Bayes, Monica ^{[10
]}

Heath, Simon ^{[10
]}

Gut, Marta ^{[10
]}

Gut, Ivo ^{[10
]}

Estivill, Xavier ^{[3
]}

Lopez-Guillermo, Armando

Puente, Xose S. ^{[1
]}

Campo, Elias ^{[2
]}

Lopez-Otin, Carlos ^{[1
]}

机构：

[1] Univ Oviedo, Inst Univ Oncol, Dept Bioquim & Biol Mol, Oviedo, Spain

[2] Univ Barcelona, Unidad Hematopatol, Serv Anat Patol, Hosp Clin,Inst Invest Biomed August Pi & Sunyer I, Barcelona, Spain

[3] Pompeu Fabra Univ CRG UPF, Ctr Genom Regulat, Genes & Dis Programme, Barcelona, Spain

[4] IDIBAPS, Unidad Genom, Barcelona, Spain

[5] Univ Barcelona, Serv Hematol, Hosp Clin, Barcelona, Spain

[6] Univ Salamanca, Serv Hematol, Univ Hosp, Ctr Invest Canc, E-37008 Salamanca, Spain

[7] Univ Barcelona, Programa Conjunto Biol Computac, BSC, IRB,Spanish Natl Bioinformat Inst, Barcelona, Spain

[8] Spanish Natl Bioinformat Inst, Spanish Natl Canc Res Ctr CNIO, Struct Biol & Biocomp Programme, Madrid, Spain

[9] CRG UPF, Ultrasequencing Unit, Barcelona, Spain

[10] Ctr Nacl Anal Genom, Barcelona, Spain

来源：

NATURE GENETICS | 2012年 / 44卷 / 01期

关键词：

PRE-MESSENGER-RNA; CANCER GENOME; SOMATIC MUTATIONS; MYELODYSPLASIA; SPLICEOSTATIN; ACTIVATION; EXPRESSION; PATHWAYS;

D O I：

10.1038/ng.1032

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：47 / 52

页数：6

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