Frequent hypermethylation of DBC1 in malignant lymphoproliferative neoplasms

Abstract

Allelic loss at chromosome 9q31-34 is a frequent event in many lymphoproliferative malignancies. Here, we examined DBC1 at 9q33.1 as a potential target in lymphomagenesis. DBC1 is a putative tumor suppressor that has been shown to be involved in the regulation of cell growth and programmed cell death. The methylation status of the DBC1 promoter CpG island was examined by methylation-specific PCR, bisulfite sequencing, and methylation-specific melting curve analysis. DBC1 was hypermethylated in 5 of 5 B-cell-derived lymphoma cell lines, 41 of 42 diffuse large B-cell lymphomas, 24 of 24 follicular lymphomas, 5 of 5 mantle cell lymphomas, 4 of 4 small lymphocytic lymphomas, 1 of 2 lymphoplasmacytoid lymphomas, and in 12 of 12 acute lymphoblastic leukemias, but was unmethylated in 1 case of splenic marginal zone lymphoma, in 12 of 12 multiple myelomas, in 24 of 24 reactive lymph nodes, and in 12 of 12 samples of blood lymphocytes from random donors. DBC1 hypermethylation was associated with transcriptional silencing in lymphoma cell lines, and reexpression of this gene could be induced by treatment with the demethylating agent, 5-aza-2 0 -deoxycytidine. Our data suggest that hypermethylation of the DBC1 promoter region is a frequent event during the development of lymphoproliferative malignancies, and that DBC1 hypermethylation may serve as a marker for these cancers.

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

“…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.…”

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

“…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.…”

“…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].…”

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

“…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.…”