Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Significance This is a comprehensive whole-genome/whole-exome analysis of mantle cell lymphoma (MCL). We sequenced 29 MCL cases and validated the findings by target sequencing of 172 additional tumors. We identified recurrent mutations in genes regulating chromatin modification and genes such as NOTCH2 that have a major impact on clinical outcome. Additionally, we demonstrated the subclonal heterogeneity of the tumors already at diagnosis and the modulation of the mutational architecture in the progression of the disease. The identification of new molecular mechanisms may open perspectives for the management of MCL patients. 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.

Manel Juan | Adrian Wiestner | Marta Aymerich | Alba Navarro | Reiner Siebert | Carlos López-Otín | Rafael Valdés-Mas | Wolfram Klapper | Dolors Colomer | Ferran Nadeu | Xose S Puente | José I Martín-Subero | María J Calasanz | Pedro Vizán | Andreas Rosenwald | Luciano Di Croce | E. Giné | A. Rosenwald | W. Wilson | W. Klapper | R. Siebert | A. López-Guillermo | E. Campo | G. Ott | A. Valera | Antonio Martínez | P. Jares | M. Pinyol | N. Villamor | X. Puente | S. Beà | R. Valdés-Mas | J. Martín-Subero | M. Aymerich | G. Clot | D. Colomer | A. Enjuanes | J. Hernández-Rivas | M. López-Guerra | D. Martín-Garcia | A. Navarro | Diana A. Puente | C. Royo | M. Rozman | I. Salaverria | C. López-Otín | L. Conde | M. Juan | M. Calasanz | A. Wiestner | G. Roué | P. Vizán | L. Di Croce | L. Colomo | E. Hartmann | Pedro Jares | German Ott | Elías Campo | Armando López-Guillermo | Eva Giné | F. Nadeu | Neus Villamor | Wyndham H Wilson | Magda Pinyol | L. Hernández | V. Amador | A. Moros | P. Forcada | A. Muntañola | Sílvia Beà | Itziar Salaverria | Cristina Royo | David Martín-Garcia | Laura Conde | Guillem Clot | Diana A Puente | Mónica López-Guerra | Alexandra Moros | Gael Roue | Lluís Colomo | Antonio Martínez | Alexandra Valera | Virginia Amador | Luis Hernández | Maria Rozman | Anna Enjuanes | Pilar Forcada | Ana Muntañola | Elena M Hartmann | Jesús M Hernández-Rivas | A. Muntañola | X. S. Puente | D. Martín-García | Alexandra Valera | W. Wilson | Pedro Vizán | Luís Hernández

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