Genome-wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features

Anna Enjuanes, Robert Albero, Guillem Clot, Alba Navarro, Sílvia Beà, Magda Pinyol, José I. Martín-Subero, Wolfram Klapper, Louis M. Staudt, Elaine S. Jaffe, Lisa Rimsza, Rita Braziel, Jan Delabie, James R. Cook, Raymond R. Tubbs, Randy Gascoyne, Joseph M. Connors, Dennis D. Weisenburger, Timothy C. Greiner, Wing Chung Chan & 5 others Armando Lõpez-Guillermo, Andreas Rosenwald, German Ott, Elías Campo, Pedro Jares

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Mantle cell lymphoma (MCL) is a B-cell neoplasm with an aggressive clinical behavior characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. To clarify the potential contribution of altered DNA methylation in the development and/or progression of MCL, we performed genome-wide methylation profiling of a large cohort of primary MCL tumors (n = 132), MCL cell lines (n = 6) and normal lymphoid tissue samples (n = 31), using the Infinium HumanMethylation27 BeadChip. DNA methylation was compared to gene expression, chromosomal alterations and clinicopathological parameters. Primary MCL displayed a heterogeneous methylation pattern dominated by DNA hypomethylation when compared to normal lymphoid samples. A total of 454 hypermethylated and 875 hypomethylated genes were identified as differentially methylated in at least 10% of primary MCL. Annotation analysis of hypermethylated genes recognized WNT pathway inhibitors and several tumor suppressor genes as frequently methylated, and a substantial fraction of these genes (22%) showed a significant downregulation of their transcriptional levels. Furthermore, we identified a subset of tumors with extensive CpG methylation that had an increased proliferation signature, higher number of chromosomal alterations and poor prognosis. Our results suggest that a subset of MCL displays a dysregulation of DNA methylation characterized by the accumulation of CpG hypermethylation highly associated with increased proliferation that may influence the clinical behavior of the tumors.

Original languageEnglish (US)
Pages (from-to)2852-2863
Number of pages12
JournalInternational Journal of Cancer
Volume133
Issue number12
DOIs
StatePublished - Dec 15 2013

Fingerprint

Mantle-Cell Lymphoma
Methylation
Genome
DNA Methylation
Neoplasms
Genes
Cyclin D1
Lymphoid Tissue
Tumor Suppressor Genes
B-Lymphocytes
Down-Regulation
Gene Expression
Cell Line
DNA

Keywords

  • genome-wide
  • hypermethylation
  • hypomethylation
  • mantle cell lymphoma
  • pathogenesis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Genome-wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features. / Enjuanes, Anna; Albero, Robert; Clot, Guillem; Navarro, Alba; Beà, Sílvia; Pinyol, Magda; Martín-Subero, José I.; Klapper, Wolfram; Staudt, Louis M.; Jaffe, Elaine S.; Rimsza, Lisa; Braziel, Rita; Delabie, Jan; Cook, James R.; Tubbs, Raymond R.; Gascoyne, Randy; Connors, Joseph M.; Weisenburger, Dennis D.; Greiner, Timothy C.; Chan, Wing Chung; Lõpez-Guillermo, Armando; Rosenwald, Andreas; Ott, German; Campo, Elías; Jares, Pedro.

In: International Journal of Cancer, Vol. 133, No. 12, 15.12.2013, p. 2852-2863.

Research output: Contribution to journalArticle

Enjuanes, A, Albero, R, Clot, G, Navarro, A, Beà, S, Pinyol, M, Martín-Subero, JI, Klapper, W, Staudt, LM, Jaffe, ES, Rimsza, L, Braziel, R, Delabie, J, Cook, JR, Tubbs, RR, Gascoyne, R, Connors, JM, Weisenburger, DD, Greiner, TC, Chan, WC, Lõpez-Guillermo, A, Rosenwald, A, Ott, G, Campo, E & Jares, P 2013, 'Genome-wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features', International Journal of Cancer, vol. 133, no. 12, pp. 2852-2863. https://doi.org/10.1002/ijc.28321
Enjuanes, Anna ; Albero, Robert ; Clot, Guillem ; Navarro, Alba ; Beà, Sílvia ; Pinyol, Magda ; Martín-Subero, José I. ; Klapper, Wolfram ; Staudt, Louis M. ; Jaffe, Elaine S. ; Rimsza, Lisa ; Braziel, Rita ; Delabie, Jan ; Cook, James R. ; Tubbs, Raymond R. ; Gascoyne, Randy ; Connors, Joseph M. ; Weisenburger, Dennis D. ; Greiner, Timothy C. ; Chan, Wing Chung ; Lõpez-Guillermo, Armando ; Rosenwald, Andreas ; Ott, German ; Campo, Elías ; Jares, Pedro. / Genome-wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features. In: International Journal of Cancer. 2013 ; Vol. 133, No. 12. pp. 2852-2863.
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abstract = "Mantle cell lymphoma (MCL) is a B-cell neoplasm with an aggressive clinical behavior characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. To clarify the potential contribution of altered DNA methylation in the development and/or progression of MCL, we performed genome-wide methylation profiling of a large cohort of primary MCL tumors (n = 132), MCL cell lines (n = 6) and normal lymphoid tissue samples (n = 31), using the Infinium HumanMethylation27 BeadChip. DNA methylation was compared to gene expression, chromosomal alterations and clinicopathological parameters. Primary MCL displayed a heterogeneous methylation pattern dominated by DNA hypomethylation when compared to normal lymphoid samples. A total of 454 hypermethylated and 875 hypomethylated genes were identified as differentially methylated in at least 10{\%} of primary MCL. Annotation analysis of hypermethylated genes recognized WNT pathway inhibitors and several tumor suppressor genes as frequently methylated, and a substantial fraction of these genes (22{\%}) showed a significant downregulation of their transcriptional levels. Furthermore, we identified a subset of tumors with extensive CpG methylation that had an increased proliferation signature, higher number of chromosomal alterations and poor prognosis. Our results suggest that a subset of MCL displays a dysregulation of DNA methylation characterized by the accumulation of CpG hypermethylation highly associated with increased proliferation that may influence the clinical behavior of the tumors.",
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T1 - Genome-wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features

AU - Enjuanes, Anna

AU - Albero, Robert

AU - Clot, Guillem

AU - Navarro, Alba

AU - Beà, Sílvia

AU - Pinyol, Magda

AU - Martín-Subero, José I.

AU - Klapper, Wolfram

AU - Staudt, Louis M.

AU - Jaffe, Elaine S.

AU - Rimsza, Lisa

AU - Braziel, Rita

AU - Delabie, Jan

AU - Cook, James R.

AU - Tubbs, Raymond R.

AU - Gascoyne, Randy

AU - Connors, Joseph M.

AU - Weisenburger, Dennis D.

AU - Greiner, Timothy C.

AU - Chan, Wing Chung

AU - Lõpez-Guillermo, Armando

AU - Rosenwald, Andreas

AU - Ott, German

AU - Campo, Elías

AU - Jares, Pedro

PY - 2013/12/15

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N2 - Mantle cell lymphoma (MCL) is a B-cell neoplasm with an aggressive clinical behavior characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. To clarify the potential contribution of altered DNA methylation in the development and/or progression of MCL, we performed genome-wide methylation profiling of a large cohort of primary MCL tumors (n = 132), MCL cell lines (n = 6) and normal lymphoid tissue samples (n = 31), using the Infinium HumanMethylation27 BeadChip. DNA methylation was compared to gene expression, chromosomal alterations and clinicopathological parameters. Primary MCL displayed a heterogeneous methylation pattern dominated by DNA hypomethylation when compared to normal lymphoid samples. A total of 454 hypermethylated and 875 hypomethylated genes were identified as differentially methylated in at least 10% of primary MCL. Annotation analysis of hypermethylated genes recognized WNT pathway inhibitors and several tumor suppressor genes as frequently methylated, and a substantial fraction of these genes (22%) showed a significant downregulation of their transcriptional levels. Furthermore, we identified a subset of tumors with extensive CpG methylation that had an increased proliferation signature, higher number of chromosomal alterations and poor prognosis. Our results suggest that a subset of MCL displays a dysregulation of DNA methylation characterized by the accumulation of CpG hypermethylation highly associated with increased proliferation that may influence the clinical behavior of the tumors.

AB - Mantle cell lymphoma (MCL) is a B-cell neoplasm with an aggressive clinical behavior characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. To clarify the potential contribution of altered DNA methylation in the development and/or progression of MCL, we performed genome-wide methylation profiling of a large cohort of primary MCL tumors (n = 132), MCL cell lines (n = 6) and normal lymphoid tissue samples (n = 31), using the Infinium HumanMethylation27 BeadChip. DNA methylation was compared to gene expression, chromosomal alterations and clinicopathological parameters. Primary MCL displayed a heterogeneous methylation pattern dominated by DNA hypomethylation when compared to normal lymphoid samples. A total of 454 hypermethylated and 875 hypomethylated genes were identified as differentially methylated in at least 10% of primary MCL. Annotation analysis of hypermethylated genes recognized WNT pathway inhibitors and several tumor suppressor genes as frequently methylated, and a substantial fraction of these genes (22%) showed a significant downregulation of their transcriptional levels. Furthermore, we identified a subset of tumors with extensive CpG methylation that had an increased proliferation signature, higher number of chromosomal alterations and poor prognosis. Our results suggest that a subset of MCL displays a dysregulation of DNA methylation characterized by the accumulation of CpG hypermethylation highly associated with increased proliferation that may influence the clinical behavior of the tumors.

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