Discovery of novel epigenetic markers in non-Hodgkin's lymphoma

Abstract

Non-Hodgkin's lymphoma (NHL) is a group of malignancies with heterogeneous genetic and epigenetic alterations. Discovery of molecular markers that better define NHL should improve diagnosis, prognosis and understanding of the biology. We developed a CpG island DNA microarray for discovery of aberrant methylation targets in cancer, and now apply this method to examine NHL cell lines and primary tumors. This methylation profiling revealed differential patterns in six cell lines originating from different subtypes of NHL. We identified 30 hypermethylated genes in these cell lines and independently confirmed 10 of them. Methylation of 6 of these genes was then further examined in 75 primary NHL specimens composed of four subtypes representing different stages of maturation. Each gene (DLC-1, PCDHGB7, CYP27B1, EFNA5, CCND1 and RARbeta2) was frequently hypermethylated in these NHLs (87, 78, 61, 53, 40 and 38%, respectively), but not in benign follicular hyperplasia. Although some genes such as DLC-1 and PCDHGB7 were methylated in the vast majority of NHLs, others were differentially methylated in specific subtypes. The methylation of the candidate tumor suppressor gene DLC-1 was detected in a high proportion of primary tumor and plasma DNA samples by using quantitative methylation-specific PCR analysis. This promoter hypermethylation inversely correlated with DLC-1 gene expression in primary NHL samples. Thus, this CpG island microarray is a powerful discovery tool to identify novel methylated genes for further studies of their relevant molecular pathways in NHLs and identification of potential epigenetic biomarkers of disease.

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

“…Flavone thus restored the expression of DLC1 in breast and colon carcinoma cell lines all of which manifest silencing of the endogenous gene as a result of promoter hypermethylation. Promoter hypermethylation is a major mechanism of DLC1 down-regulation and inactivation in many other types of solid tumors and hematological malignancies [13,17,49], and reactivation of DLC1 expression by dietary constituents thus warrants further investigation. Various dietary compounds have been shown to have potential therapeutic benefits [48,50,51,52].…”

DNA methylation profiles in diffuse large B-cell lymphoma and their relationship to gene expression status

“…Although widespread epigenetic analyses could yield insights into disease origins and provide diagnostic and prognostic biomarkers, larger scale studies have focused on NHL cell lines. 11 Here, we have taken the initial steps in the widespread epigenetic characterization of DLBCL by comparing the DNA methylation levels of over 500 gene-associated CpG islands in tumors. Using a twophase methylation screening strategy, we identified genes that are frequently methylated in all DLBCL tumors and uncovered evidence of epigenetic differences between ABC-DLBCL and GCB-DLBCL tumor subtypes.…”

Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities

“…Its expression is frequently downregulated or silenced in various solid tumors and hematologic malignancies, predominantly by promoter methylation (6)(7)(8)(9)(10)(11)(12)(13). Ectopic reexpression in DLC1-deficient cancer cell lines can suppress cell proliferation, induce apoptosis, and reduce tumorigenicity.…”