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Precision Medicine and Imaging

A Cyclin D1–Dependent Transcriptional Program Predicts Clinical Outcome in Mantle Cell Lymphoma

Santiago Demajo, Robert Albero, Guillem Clot, Giancarlo Castellano, Alba Navarro, Cristina Capdevila, Anna Enjuanes, Ferran Nadeu, Eva Giné, Magda Pinyol, Elaine S. Jaffe, German Ott, Louis M. Staudt, Andreas Rosenwald, David W. Scott, Lisa M. Rimsza, Armando López-Guillermo, Sílvia Beà, Elias Campo and Pedro Jares
Santiago Demajo
1Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
2Department of Pathology and Experimental Therapeutics, School of Medicine, University of Barcelona, Barcelona, Spain.
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  • ORCID record for Santiago Demajo
Robert Albero
1Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
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Guillem Clot
1Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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Giancarlo Castellano
4Genomics Unit, IDIBAPS, Barcelona, Spain.
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Alba Navarro
1Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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Cristina Capdevila
1Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
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Anna Enjuanes
3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
4Genomics Unit, IDIBAPS, Barcelona, Spain.
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Ferran Nadeu
1Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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Eva Giné
1Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
5Hematology Department, Hospital Clinic of Barcelona, Barcelona, Spain.
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Magda Pinyol
3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
4Genomics Unit, IDIBAPS, Barcelona, Spain.
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Elaine S. Jaffe
6Hematopathology Section, NCI, Bethesda, Maryland.
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German Ott
7Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
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Louis M. Staudt
8Center for Cancer Research, Lymphoid Malignancies Branch, NCI, Bethesda, Maryland.
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Andreas Rosenwald
9Institute of Pathology, University of Würzburg, Würzburg, Germany.
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David W. Scott
10Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
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Lisa M. Rimsza
11Department of Pathology, Mayo Clinic, Scottsdale, Arizona.
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Armando López-Guillermo
1Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
5Hematology Department, Hospital Clinic of Barcelona, Barcelona, Spain.
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Sílvia Beà
1Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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Elias Campo
1Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
12Hematopathology Unit, Department of Anatomic Pathology, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.
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Pedro Jares
1Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
12Hematopathology Unit, Department of Anatomic Pathology, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.
13Molecular Biology Core, Hospital Clinic of Barcelona, Barcelona, Spain.
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  • For correspondence: pjares@clinic.cat
DOI: 10.1158/1078-0432.CCR-20-2868 Published January 2021
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Abstract

Purpose: Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression. Cyclin D1 is a major cell-cycle regulator and also regulates transcription, but the impact of cyclin D1–mediated transcriptional dysregulation on MCL pathogenesis remains poorly understood. The aim of this study was to define a cyclin D1–dependent gene expression program and analyze its prognostic value.

Experimental Design: We integrated genome-wide expression analysis of cyclin D1–silenced and overexpressing cells with cyclin D1 chromatin-binding profiles to identify a cyclin D1–dependent transcriptional program in MCL cells. We analyzed this gene program in two MCL series of peripheral blood samples (n = 53) and lymphoid tissues (n = 106) to determine its biological and clinical relevance. We then obtained a simplified signature of this program and evaluated a third series of peripheral blood MCL samples (n = 81) by NanoString gene expression profiling to validate our findings.

Results: We identified a cyclin D1–dependent transcriptional program composed of 295 genes that were mainly involved in cell-cycle control. The cyclin D1–dependent gene program was overexpressed in MCL tumors directly proportional to cyclin D1 levels. High expression of this program conferred an adverse prognosis with significant shorter overall survival of the patients. These observations were validated in an independent cohort of patients using a simplified 37-gene cyclin D1 signature. The cyclin D1–dependent transcriptional program was also present in multiple myeloma and breast tumors with cyclin D1 overexpression.

Conclusions: We identified a cyclin D1–dependent transcriptional program that is overexpressed in MCL and predicts clinical outcome.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2021;27:213–25

  • Received July 23, 2020.
  • Revision received September 16, 2020.
  • Accepted October 7, 2020.
  • Published first October 12, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 27 (1)
January 2021
Volume 27, Issue 1
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A Cyclin D1–Dependent Transcriptional Program Predicts Clinical Outcome in Mantle Cell Lymphoma
Santiago Demajo, Robert Albero, Guillem Clot, Giancarlo Castellano, Alba Navarro, Cristina Capdevila, Anna Enjuanes, Ferran Nadeu, Eva Giné, Magda Pinyol, Elaine S. Jaffe, German Ott, Louis M. Staudt, Andreas Rosenwald, David W. Scott, Lisa M. Rimsza, Armando López-Guillermo, Sílvia Beà, Elias Campo and Pedro Jares
Clin Cancer Res January 1 2021 (27) (1) 213-225; DOI: 10.1158/1078-0432.CCR-20-2868

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A Cyclin D1–Dependent Transcriptional Program Predicts Clinical Outcome in Mantle Cell Lymphoma
Santiago Demajo, Robert Albero, Guillem Clot, Giancarlo Castellano, Alba Navarro, Cristina Capdevila, Anna Enjuanes, Ferran Nadeu, Eva Giné, Magda Pinyol, Elaine S. Jaffe, German Ott, Louis M. Staudt, Andreas Rosenwald, David W. Scott, Lisa M. Rimsza, Armando López-Guillermo, Sílvia Beà, Elias Campo and Pedro Jares
Clin Cancer Res January 1 2021 (27) (1) 213-225; DOI: 10.1158/1078-0432.CCR-20-2868
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