Tumor-Specific Methylation of the 8p22 Tumor Suppressor Gene DLC1 is an Epigenetic Biomarker for Hodgkin, Nasal NK/T-Cell and Other Types of Lymphomas

Abstract

Aberrant promoter methylation is an epigenetic mechanism for silencing tumor suppressor genes (TSG), and is also a biomarker for early cancer diagnosis and prognosis prediction. Recently, we and others identified DLC1 (ARHGAP7) as a functional TSG frequently methylated in multiple carcinomas. Here, we further uncovered DLC1 as one of the up-regulated genes in lymphoma cell lines after pharmacologic demethylation with 5-aza-2’-deoxycytidine (Aza). Transcriptional silencing and methylation of DLC1 was detected in most Hodgkin (HL) and non-Hodgkin lymphoma (NHL) cell lines, including 4/6 Hodgkin, 4/4 nasal NK/T-cell, 6/6 Burkitt and 5/5 diffuse large B-cell lymphoma cell lines. Aza treatment led to DLC1 promoter demethylation and transcriptional reactivation in silenced cell lines, indicating a methylation-mediated silencing. Aberrant methylation was further detected in 44% (14/37) Hodgkin, 77% (34/44) nasal NK/T-cell and 60-90% of various types of primary NHLs, but not in any normal lymph node or PBMC sample, and is thus tumor-specific. Analysis of microdissected Hodgkin/Reed-Sternberg (HRS) cells from HL cases confirmed the site of methylation as tumor cells. Moreover, DLC1 methylation was detected in 4/14 (29%) serum samples from HL patients. Our results indicate that DLC1 methylation is a frequent event in multiple lymphomagenesis and could serve as a tumor-specific biomarker for future lymphoma diagnosis.