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Research Article

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 Aymerich, Neus 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, and Elías Campo
  1. aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
  2. bInstituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain;
  3. cCenter for Genomic Regulation and Universitat Pompeu Fabra, 08003 Barcelona, Spain;
  4. dMutua de Terrassa, 08221 Terrassa, Spain;
  5. eInstitute of Pathology, University of Würzburg, 97080 Würzburg, Germany;
  6. fDepartamento de Genética, Universidad de Navarra, 31080 Pamplona, Spain;
  7. gRobert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany;
  8. hCentro de Investigación del Cáncer, Universidad de Salamanca, 37007 Salamanca, Spain;
  9. iHematopathology Section and Lymph Node Registry, University of Kiel, D-24105 Kiel, Germany;
  10. jInstitute of Human Genetics, University of Kiel, D-24105 Kiel, Germany;
  11. kNational Heart, Lung, and Blood Institute, Bethesda, MD 20892; and
  12. lNational Cancer Institute, Bethesda, MD 20892

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PNAS first published October 21, 2013; https://doi.org/10.1073/pnas.1314608110
Sílvia Beà
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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  • For correspondence: ecampo@clinic.ub.es sbea@clinic.ub.es xspuente@uniovi.es
Rafael Valdés-Mas
bInstituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain;
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Alba Navarro
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Itziar Salaverria
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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David Martín-Garcia
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Pedro Jares
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Eva Giné
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Magda Pinyol
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Cristina Royo
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Ferran Nadeu
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Laura Conde
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Manel Juan
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Guillem Clot
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Pedro Vizán
cCenter for Genomic Regulation and Universitat Pompeu Fabra, 08003 Barcelona, Spain;
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Luciano Di Croce
cCenter for Genomic Regulation and Universitat Pompeu Fabra, 08003 Barcelona, Spain;
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Diana A. Puente
bInstituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain;
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Mónica López-Guerra
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Alexandra Moros
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Gael Roue
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Marta Aymerich
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Neus Villamor
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Lluís Colomo
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Antonio Martínez
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Alexandra Valera
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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José I. Martín-Subero
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Virginia Amador
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Luis Hernández
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Maria Rozman
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Anna Enjuanes
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Pilar Forcada
dMutua de Terrassa, 08221 Terrassa, Spain;
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Ana Muntañola
dMutua de Terrassa, 08221 Terrassa, Spain;
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Elena M. Hartmann
eInstitute of Pathology, University of Würzburg, 97080 Würzburg, Germany;
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María J. Calasanz
fDepartamento de Genética, Universidad de Navarra, 31080 Pamplona, Spain;
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Andreas Rosenwald
eInstitute of Pathology, University of Würzburg, 97080 Würzburg, Germany;
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German Ott
gRobert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany;
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Jesús M. Hernández-Rivas
hCentro de Investigación del Cáncer, Universidad de Salamanca, 37007 Salamanca, Spain;
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Wolfram Klapper
iHematopathology Section and Lymph Node Registry, University of Kiel, D-24105 Kiel, Germany;
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Reiner Siebert
jInstitute of Human Genetics, University of Kiel, D-24105 Kiel, Germany;
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Adrian Wiestner
kNational Heart, Lung, and Blood Institute, Bethesda, MD 20892; and
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Wyndham H. Wilson
lNational Cancer Institute, Bethesda, MD 20892
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Dolors Colomer
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Armando López-Guillermo
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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Carlos López-Otín
bInstituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain;
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Xose S. Puente
bInstituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain;
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  • For correspondence: ecampo@clinic.ub.es sbea@clinic.ub.es xspuente@uniovi.es
Elías Campo
aInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain;
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  • For correspondence: ecampo@clinic.ub.es sbea@clinic.ub.es xspuente@uniovi.es
  1. Edited* by Louis M. Staudt, National Institutes of Health, Bethesda, MD, and approved September 19, 2013 (received for review August 7, 2013)

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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.

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.

  • next-generation sequencing
  • cancer genetics
  • cancer heterogeneity

Footnotes

  • ↵1To whom correspondence may be addressed. E-mail: ecampo{at}clinic.ub.es, sbea{at}clinic.ub.es, or xspuente{at}uniovi.es.
  • ↵2C.L.-O., X.S.P., and E.C. contributed equally to this work.

  • Author contributions: S.B., C.L.-O., X.S.P., and E.C. designed research; S.B., R.V.-M., A.N., I.S., D.M.-G., P.J., M.P., C.R., F.N., L. Conde, M.J., P.V., L.D.C., D.A.P., M.L.-G., A. Moros, G.R., L. Colomo, A. Martínez, A.V., J.I.M.-S., V.A., L.H., A.E., R.S., and E.C. performed research; P.V., L.D.C., M.A., P.F., A. Muntañola, E.M.H., A.R., G.O., J.M.H.-R., W.K., R.S., A.W., W.H.W., and D.C. contributed new reagents/analytic tools; S.B., R.V.-M., A.N., I.S., D.M.-G., P.J., E.G., M.P., C.R., M.J., G.C., G.R., N.V., J.I.M.-S., M.R., M.J.C., R.S., D.C., A.L.-G., C.L.-O., X.S.P., and E.C. analyzed data; and S.B., C.L.-O., X.S.P., and E.C. wrote the paper.

  • The authors declare no conflict of interest.

  • ↵*This Direct Submission article had a prearranged editor.

  • Data deposition: Next-generation sequencing data have been deposited at the European Genome-Phenome Archive under accession no. EGAS00001000510. Affymetrix SNP6.0 array and HU133+2.0 gene expression data have been deposited at Gene Expression Omnibus (GEO) under accession nos. GSE46969 and GSE36000, respectively.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1314608110/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Next-generation sequencing of 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 Aymerich, Neus 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
Proceedings of the National Academy of Sciences Oct 2013, 201314608; DOI: 10.1073/pnas.1314608110

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Next-generation sequencing of 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 Aymerich, Neus 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
Proceedings of the National Academy of Sciences Oct 2013, 201314608; DOI: 10.1073/pnas.1314608110
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