title: Landscape of somatic mutations and clonal evolution in mantle cell lymphoma.
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.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Beà
authors.forename: Rafael
authors.initials: R
authors.lastname: Valdés-Mas
authors.forename: Alba
authors.initials: A
authors.lastname: Navarro
authors.forename: Itziar
authors.initials: I
authors.lastname: Salaverria
authors.forename: David
authors.initials: D
authors.lastname: Martín-Garcia
authors.forename: Pedro
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authors.lastname: Jares
authors.forename: Eva
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authors.lastname: Giné
authors.forename: Magda
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authors.lastname: Pinyol
authors.forename: Cristina
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authors.lastname: Royo
authors.forename: Ferran
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authors.lastname: Nadeu
authors.forename: Laura
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authors.lastname: Conde
authors.forename: Manel
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authors.lastname: Juan
authors.forename: Guillem
authors.initials: G
authors.lastname: Clot
authors.forename: Pedro
authors.initials: P
authors.lastname: Vizán
authors.forename: Luciano
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authors.lastname: Di Croce
authors.forename: Diana A
authors.initials: DA
authors.lastname: Puente
authors.forename: Mónica
authors.initials: M
authors.lastname: López-Guerra
authors.forename: Alexandra
authors.initials: A
authors.lastname: Moros
authors.forename: Gael
authors.initials: G
authors.lastname: Roue
authors.forename: Marta
authors.initials: M
authors.lastname: Aymerich
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.forename: Lluís
authors.initials: L
authors.lastname: Colomo
authors.forename: Antonio
authors.initials: A
authors.lastname: Martínez
authors.forename: Alexandra
authors.initials: A
authors.lastname: Valera
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.forename: Virginia
authors.initials: V
authors.lastname: Amador
authors.forename: Luis
authors.initials: L
authors.lastname: Hernández
authors.forename: Maria
authors.initials: M
authors.lastname: Rozman
authors.forename: Anna
authors.initials: A
authors.lastname: Enjuanes
authors.forename: Pilar
authors.initials: P
authors.lastname: Forcada
authors.forename: Ana
authors.initials: A
authors.lastname: Muntañola
authors.forename: Elena M
authors.initials: EM
authors.lastname: Hartmann
authors.forename: María J
authors.initials: MJ
authors.lastname: Calasanz
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Hernández-Rivas
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.forename: Armando
authors.initials: A
authors.lastname: López-Guillermo
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Xose S
authors.initials: XS
authors.lastname: Puente
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D001483:Base Sequence; D060965:Clonal Evolution / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000503:physiopathology; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D051883:Receptor, Notch2 / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics
chemical_list: C530104:CCND1 protein, human; C497764:NOTCH2 protein, human; D051883:Receptor, Notch2; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D019938:Cyclin D1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: cancer genetics; cancer heterogeneity; next-generation sequencing