Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

被引：419

作者：

Bea, Silvia ^{[1
]}

Valdes-Mas, Rafael ^{[2
]}

Navarro, Alba ^{[1
]}

Salaverria, Itziar ^{[1
]}

Martin-Garcia, David ^{[1
]}

Jares, Pedro ^{[1
]}

Gine, Eva ^{[1
]}

Pinyol, Magda ^{[1
]}

Royo, Cristina ^{[1
]}

Nadeu, Ferran ^{[1
]}

Conde, Laura ^{[1
]}

Juan, Manel ^{[1
]}

Clot, Guillem ^{[1
]}

Vizan, Pedro ^{[3
,4
]}

Di Croce, Luciano ^{[3
,4
]}

Puente, Diana A. ^{[2
]}

Lopez-Guerra, Monica ^{[1
]}

Moros, Alexandra ^{[1
]}

Roue, Gael ^{[1
]}

Aymerich, Marta ^{[1
]}

Villamor, Neus ^{[1
]}

Colomo, Lluis ^{[1
]}

Martinez, Antonio ^{[1
]}

Valera, Alexandra ^{[1
]}

Martin-Subero, Jose I. ^{[1
]}

Amador, Virginia ^{[1
]}

Hernandez, Luis ^{[1
]}

Rozman, Maria ^{[1
]}

Enjuanes, Anna ^{[1
]}

Forcada, Pilar ^{[5
]}

Muntanola, Ana ^{[5
]}

Hartmann, Elena M. ^{[6
]}

Calasanz, Maria J. ^{[7
]}

Rosenwald, Andreas ^{[6
]}

Ott, German ^{[8
,9
]}

Hernandez-Rivas, Jesus M. ^{[10
]}

Klapper, Wolfram ^{[11
,12
]}

Siebert, Reiner ^{[13
]}

Wiestner, Adrian ^{[14
]}

Wilson, Wyndham H. ^{[15
]}

Colomer, Dolors ^{[1
]}

Lopez-Guillermo, Armando ^{[1
]}

Lopez-Otin, Carlos ^{[2
]}

Puente, Xose S. ^{[2
]}

Campo, Elias ^{[1
]}

机构：

[1] Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi i Sunyer, E-08036 Barcelona, Spain

[2] Univ Oviedo, Inst Univ Oncol, E-33006 Oviedo, Spain

[3] Ctr Genom Regulat, Barcelona 08003, Spain

[4] Univ Pompeu Fabra, Barcelona 08003, Spain

[5] Mutua Terrassa, Terrassa 08221, Spain

[6] Univ Wurzburg, Inst Pathol, D-97080 Wurzburg, Germany

[7] Univ Navarra, Dept Genet, E-31080 Pamplona, Spain

[8] Robert Bosch Krankenhaus, D-70376 Stuttgart, Germany

[9] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany

[10] Univ Salamanca, Ctr Invest Canc, Salamanca 37007, Spain

[11] Univ Kiel, Hematopathol Sect, D-24105 Kiel, Germany

[12] Univ Kiel, Lymph Node Registry, D-24105 Kiel, Germany

[13] Univ Kiel, Inst Human Genet, D-24105 Kiel, Germany

[14] NHLBI, Bethesda, MD 20892 USA

[15] NCI, Bethesda, MD 20892 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 45期

关键词：

next-generation sequencing; cancer genetics; cancer heterogeneity; CHRONIC LYMPHOCYTIC-LEUKEMIA; MARGINAL ZONE LYMPHOMA; GENE-EXPRESSION; MULTIPLE-MYELOMA; GOOD PROGNOSIS; CODING GENOME; C-MYC; NOTCH1; HETEROGENEITY; SIGNATURES;

D O I：

10.1073/pnas.1314608110

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：

Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.

引用

页码：18250 / 18255

页数：6

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