title: 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.
authors.affiliation: Cancer Epigenetics Laboratory, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Ying
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
authors.forename: Paul
authors.initials: P
authors.lastname: Murray
authors.forename: Zifen
authors.initials: Z
authors.lastname: Gao
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Yajun
authors.initials: Y
authors.lastname: Wang
authors.forename: Kwan Yeung
authors.initials: KY
authors.lastname: Lee
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.forename: Richard F
authors.initials: RF
authors.lastname: Ambinder
authors.forename: Gopesh
authors.initials: G
authors.lastname: Srivastava
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
mesh_terms: D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D020690:GTPase-Activating Proteins; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008223:Lymphoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D009669:Nose Neoplasms / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C112352:DLC1 protein, human; D004273:DNA, Neoplasm; D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins