Frequent hypermethylation of DBC1 in malignant lymphoproliferative neoplasms

Grønbæk, Kirsten; Ralfkiær, Ulrik; Dahl, Christina; Hother, Christoffer; Burns, Jorge S.; Kassem, Moustapha; Worm, Jesper; Ralfkiær, Elisabeth; Knudsen, Lene Meldgaard; Hokland, Peter; Guldberg, Per

doi:10.1038/modpathol.2008.27

Cited by 22 publications

(11 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DBC1 , DIO3 , FZD9 , HS3ST2 , MOS and MYOD1 , that were significantly hypermethylated in B-cell, T-cell and myeloid malignancies. Hypermethylation of DBC1, HS3ST2 and MYOD1 has been reported before not only in HNs [12], [18], [34], [35], [36], [37] but also in solid tumors [38], [39], [40]. Therefore, silencing of these genes by hypermethylation seems to be a frequent pathomechanism associated with most human cancers.…”

Section: Discussionmentioning

confidence: 84%

A Comprehensive Microarray-Based DNA Methylation Study of 367 Hematological Neoplasms

et al. 2009

View full text Add to dashboard Cite

BackgroundAlterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required.Methodology/Principal FindingsHere, we report for the first time a microarray-based DNA methylation study of 767 genes in 367 HNs diagnosed with 16 of the most representative B-cell (n = 203), T-cell (n = 30), and myeloid (n = 134) neoplasias, as well as 37 samples from different cell types of the hematopoietic system. Using appropriate controls of B-, T-, or myeloid cellular origin, we identified a total of 220 genes hypermethylated in at least one HN entity. In general, promoter hypermethylation was more frequent in lymphoid malignancies than in myeloid malignancies, being germinal center mature B-cell lymphomas as well as B and T precursor lymphoid neoplasias those entities with highest frequency of gene-associated DNA hypermethylation. We also observed a significant correlation between the number of hypermethylated and hypomethylated genes in several mature B-cell neoplasias, but not in precursor B- and T-cell leukemias. Most of the genes becoming hypermethylated contained promoters with high CpG content, and a significant fraction of them are targets of the polycomb repressor complex. Interestingly, T-cell prolymphocytic leukemias show low levels of DNA hypermethylation and a comparatively large number of hypomethylated genes, many of them showing an increased gene expression.Conclusions/SignificanceWe have characterized the DNA methylation profile of a wide range of different HNs entities. As well as identifying genes showing aberrant DNA methylation in certain HN subtypes, we also detected six genes—DBC1, DIO3, FZD9, HS3ST2, MOS, and MYOD1—that were significantly hypermethylated in B-cell, T-cell, and myeloid malignancies. These might therefore play an important role in the development of different HNs.

show abstract

Section: Discussionmentioning

confidence: 84%

A Comprehensive Microarray-Based DNA Methylation Study of 367 Hematological Neoplasms

et al. 2009

View full text Add to dashboard Cite

show abstract

“…This silencing mechanism has been postulated as an early and age-independent event in the development of malignancy [35], [38]. We identified aberrant methylation of DBC1 , located at 9q33.1, as an adverse prognostic marker in the AML subgroup with a normal karyotype.…”

Section: Discussionmentioning

confidence: 86%

“…Hypermethylation associated with reversible epigenetic silencing of DBC1 has been reported in hematological disorders [19], [35], [36] and in solid tumors [37], [38]. This silencing mechanism has been postulated as an early and age-independent event in the development of malignancy [35], [38].…”

Section: Discussionmentioning

confidence: 95%

DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia

et al. 2010

View full text Add to dashboard Cite

BackgroundAberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required.Methodology/Principal FindingsWe carried out high-throughput methylation profiling on 116 de novo AML cases and we validated the significant biomarkers in an independent cohort of 244 AML cases. Methylation signatures were associated with the presence of a specific cytogenetic status. In normal karyotype cases, aberrant methylation of the promoter of DBC1 was validated as a predictor of the disease-free and overall survival. Furthermore, DBC1 expression was significantly silenced in the aberrantly methylated samples. Patients with chromosome rearrangements showed distinct methylation signatures. To establish the role of fusion proteins in the epigenetic profiles, 20 additional samples of human hematopoietic stem/progenitor cells (HSPC) transduced with common fusion genes were studied and compared with patient samples carrying the same rearrangements. The presence of MLL rearrangements in HSPC induced the methylation profile observed in the MLL-positive primary samples. In contrast, fusion genes such as AML1/ETO or CBFB/MYH11 failed to reproduce the epigenetic signature observed in the patients.Conclusions/SignificanceOur study provides a comprehensive epigenetic profiling of AML, identifies new clinical markers for cases with a normal karyotype, and reveals relevant biological information related to the role of fusion proteins on the methylation signature.

show abstract

“…5 The finding that genes of the meL/umC group show low or reduced expression in maB-NHL is in complete agreement with recent studies on, for example, DCC, EPHA7, DBC1, or HTR1B applying quantitative reverse-transcription (qRT)-PCR and Northern blot techniques. [41][42][43][44] The meL/umC group was significantly enriched for genes encoding proteins involved in signal transduction pathways such as phospholipase C activation, G-protein signaling, and second messenger-mediated signaling. Interestingly, genes previously identified as hypermethylated in solid tumors are also enriched for the very same signal transduction pathways.…”

Section: Discussionmentioning

confidence: 99%

New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling

Martín‐Subero

Kreuz

Bibikova

et al. 2009

Blood

136

155

View full text Add to dashboard Cite

Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic, and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) characterized for their morphologic, genetic, and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchic clustering indicated that methylation patterns in maB-NHLs were not strictly associated with morphologic, genetic, or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype-specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHLs studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in nonhematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHLs with different morphologic, genetic, and transcriptional background share a similar stem cell-like epigenetic pattern. This suggests that maB-NHLs originate from cells with stem cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling. (Blood. 2009; 113:2488-2497 IntroductionAberrant DNA methylation is a hallmark of cancer. Virtually all cancer types are associated with alterations of the methylome. These include global DNA hypomethylation, mostly targeting DNA repeats, and hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes. [1][2][3][4] It is widely accepted that tumor suppressor gene inactivation by DNA hypermethylation allows the tumor clone to obtain a selective (eg, proliferative) advantage. However, recent reports have provided evidence for an instructive mechanism behind aberrant DNA methylation in cancer, which might indicate that specific sequences are predisposed to acquire epigenetic alterations. [5][6][7][8][9] Remarkably, 3 independent reports have recently shown that a highly significant proportion of genes becoming hypermethylated in cancer were already repressed at the embryonic stem cell (ESC) stage by polycomb group (PcG) marks. 7-9 These findings are considered to support the "cancer stem cell theory" in which The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 13, 2018. by guest www.bloodjournal.org From aberrant epigenetic changes of PcG target genes occurring in a cell with stem cell features might represent the ...

show abstract

Frequent hypermethylation of DBC1 in malignant lymphoproliferative neoplasms

Cited by 22 publications

References 38 publications

A Comprehensive Microarray-Based DNA Methylation Study of 367 Hematological Neoplasms

A Comprehensive Microarray-Based DNA Methylation Study of 367 Hematological Neoplasms

DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia

New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling

Contact Info

Product

Resources

About