Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

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

Research output: Indexed journal article Articlepeer-review

423 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)18250-18255
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number45
DOIs
Publication statusPublished - 5 Nov 2013
Externally publishedYes

Keywords

  • Cancer genetics
  • Cancer heterogeneity
  • Next-generation sequencing

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