Promoter hypermethylation of multiple genes in hydatidiform mole and choriocarcinoma.
The methylation status of genes in hydatidiform mole and choriocarcinoma and its significance is relatively unexplored. We investigated the methylation status of the promoter regions of six genes, p16, HIC-1, TIMP3, GSTP1, death-associated protein kinase (DAPK), and E-cadherin in 54 hydatidiform moles, five choriocarcinomas, and 10 first trimester placenta by methylation-specific polymerase chain reaction (PCR). Immunohistochemical expression of p16, TIMP3, and E-cadherin, and quantitative real-time RT-PCR of p16 was also performed. Among the six genes examined, the promoter region of four genes (E-cadherin, HIC-1, p16, TIMP3) in choriocarcinoma and three genes (E-cadherin, HIC-1, p16) in hydatidiform mole exhibited aberrant methylation whereas none was hypermethylated in normal placenta. There was a significant correlation between methylation and reduced expression of p16, E-cadherin, and TIMP3 (P < 0.001). Fifteen of the 54 patients with hydatidiform mole developed gestational trophoblastic neoplasia requiring chemotherapy. Promoter hypermethylation of p16 alone, or combined with E-cadherin, was significantly correlated to such development (P = 0.001, 0.0005, respectively). Hypermethylation of multiple genes, especially p16, might be related to the subsequent development of gestational trophoblastic neoplasia.
Xue
Wei-Cheng
WC
Department of Pathology, Hong Kong Jockey Club Clinical Research Centre, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China.
Chan
Kelvin Y K
KY
Feng
Hui-Chen
HC
Chiu
Pui-Man
PM
Ngan
Hextan Y S
HY
Tsao
Sai-Wah
SW
Cheung
Annie N Y
AN
D051017:Apoptosis Regulatory Proteins; D015820:Cadherins / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D002822:Choriocarcinoma / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D064550:Death-Associated Protein Kinases; D005260:Female; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D006828:Hydatidiform Mole / Q000235:genetics*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics; D051741:Kruppel-Like Transcription Factors; D010920:Placenta / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D004268:DNA-Binding Proteins; C499808:HIC1 protein, human; D007527:Isoenzymes; D051741:Kruppel-Like Transcription Factors; D019717:Tissue Inhibitor of Metalloproteinase-3; D014157:Transcription Factors; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases