title: Genome-wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features.
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.
authors.affiliation: Genomics Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Enjuanes
authors.forename: Robert
authors.initials: R
authors.lastname: Albero
authors.forename: Guillem
authors.initials: G
authors.lastname: Clot
authors.forename: Alba
authors.initials: A
authors.lastname: Navarro
authors.forename: Sílvia
authors.initials: S
authors.lastname: Beà
authors.forename: Magda
authors.initials: M
authors.lastname: Pinyol
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: Lisa
authors.initials: L
authors.lastname: Rimsza
authors.forename: Rita M
authors.initials: RM
authors.lastname: Braziel
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.forename: James R
authors.initials: JR
authors.lastname: Cook
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tubbs
authors.forename: Randy
authors.initials: R
authors.lastname: Gascoyne
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Greiner
authors.forename: Wing-Chung
authors.initials: WC
authors.lastname: Chan
authors.forename: Armando
authors.initials: A
authors.lastname: López-Guillermo
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
authors.forename: Pedro
authors.initials: P
authors.lastname: Jares
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000502:physiology
keywords: genome-wide; hypermethylation; hypomethylation; mantle cell lymphoma; pathogenesis