Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

被引:1193
作者
Puente, Xose S. [2 ]
Pinyol, Magda [3 ]
Quesada, Victor [2 ]
Conde, Laura [1 ]
Ordonez, Gonzalo R. [2 ]
Villamor, Neus [1 ]
Escaramis, Georgia [4 ]
Jares, Pedro [1 ]
Bea, Silvia [1 ]
Gonzalez-Diaz, Marcos [5 ]
Bassaganyas, Laia [4 ]
Baumann, Tycho [6 ]
Juan, Manel [7 ]
Lopez-Guerra, Monica [1 ]
Colomer, Dolors [1 ]
Tubio, Jose M. C. [4 ,8 ]
Lopez, Cristina [1 ]
Navarro, Alba [1 ]
Tornador, Cristian [4 ]
Aymerich, Marta [1 ]
Rozman, Maria [1 ]
Hernandez, Jesus M. [5 ]
Puente, Diana A. [2 ]
Freije, Jose M. P. [2 ]
Velasco, Gloria [2 ]
Gutierrez-Fernandez, Ana [2 ]
Costa, Dolors [1 ]
Carrio, Anna [1 ]
Guijarro, Sara [1 ]
Enjuanes, Anna [1 ]
Hernandez, Lluis [1 ]
Yaguee, Jordi [7 ]
Nicolas, Pilar [9 ]
Romeo-Casabona, Carlos M. [9 ]
Himmelbauer, Heinz [10 ]
Castillo, Ester [10 ]
Dohm, Juliane C. [10 ]
de Sanjose, Silvia [11 ]
Piris, Miguel A. [12 ]
de Alava, Enrique [5 ]
Miguel, Jesus San [5 ]
Royo, Romina [13 ]
Gelpi, Josep L. [13 ]
Torrents, David [13 ]
Orozco, Modesto [13 ]
Pisano, David G. [14 ]
Valencia, Alfonso [14 ]
Guigo, Roderic [15 ]
Bayes, Monica [16 ]
Heath, Simon [16 ]
机构
[1] Univ Barcelona, IDIBAPS, Hosp Clin, Serv Anat Patol,Unidad Hematopatol, E-08036 Barcelona, Spain
[2] Univ Oviedo, Inst Univ Oncol, Dept Bioquim & Biol Mol, E-33006 Oviedo, Spain
[3] IDIBAPS, Unidad Genom, Barcelona 08036, Spain
[4] Pompeu Fabra Univ, Ctr Genom Regulat, Genes & Dis Programme, Barcelona 08003, Spain
[5] Univ Salamanca, Ctr Invest Canc IBMCC USAL CSIC, Univ Hosp, Serv Hematol, Salamanca 37007, Spain
[6] Univ Barcelona, IDIBAPS, Hosp Clin, Serv Hematol, E-08036 Barcelona, Spain
[7] IDIBAPS, Hosp Clin, Serv Inmunol, Barcelona 08036, Spain
[8] Hosp Clin Univ Santiago de Compostela, Santiago De Compostela 15706, Spain
[9] Univ Basque Country, Univ Deusto, Catedra Interuniv Derechoy Genoma Humano, Bilbao 48007, Spain
[10] Pompeii Fabra Univ, Ctr Genom Regulat, Ultrasequencing Unit, Barcelona 08003, Spain
[11] IDIBELL, Inst Catala Oncol, Unidad Infecc & Canc, Lhospitalet De Llobregat 08907, Spain
[12] Spanish Natl Canc Res Ctr CNIO, Mol Pathol Programme, Madrid 28029, Spain
[13] Univ Barcelona, Spanish Natl Bioinformat Inst, IRB, Programa Conjunto Biol Computac,BSC, E-08028 Barcelona, Spain
[14] Spanish Natl Bioinformat Inst, Spanish Natl Canc Res Ctr CNIO, Struct Biol & Biocomp Programme, Madrid 28029, Spain
[15] Pompeu Fabra Univ, Ctr Genom Regulat, Spanish Natl Bioinformat Inst, Genom Bioinformat Programme, Barcelona 08003, Spain
[16] Ctr Nacl Anal Genom, Barcelona 08028, Spain
[17] CSIC, Ctr Nacl Biotecnol, E-28049 Madrid, Spain
[18] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England
关键词
CANCER GENOME; B-CLL; EXPRESSION; NOTCH1; CELLS; HYPERMUTATION; NETWORK;
D O I
10.1038/nature10113
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution(1,2). Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes(3,4). The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.
引用
收藏
页码:101 / 105
页数:5
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