Tumor-specific methylation of the 8p22 tumor suppressor gene DLC1 is an epigenetic biomaker for Hodgkin, nasal NK/T-cell and other types of lymphomas

Jianming Ying, Hongyu Li, Paul Murray, Zifen Gao, Yun Wen Chen, Yajun Wang, Kwan Yeung Lee, Anthony T.C. Chan, Richard F. Ambinder, Gopesh Srivastava, Qian Tao

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant promoter methylation is an epigenetic mechanism for silencing tumor suppresor 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.

Original languageEnglish (US)
Pages (from-to)15-21
Number of pages7
JournalEpigenetics
Volume2
Issue number1
DOIs
StatePublished - 2007

Keywords

  • Biomarker
  • DLC1
  • Lymphoma
  • Methylation
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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