Promoter Hypermethylation of Multiple Genes in Hydatidiform Mole and Choriocarcinoma

Abstract

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. (J Mol Diagn 2004, 6:326 -334)

Downregulation of ASPP1 in gestational trophoblastic disease: correlation with hypermethylation, apoptotic activity and clinical outcome

“…DNA hypermethylation of tumor-suppressor genes and stem cell transcription factors has indeed been reported in gestational trophoblastic disease. 24,26,30 Moreover, synergistic reactivation of ASPP1 mRNA expression could be observed in combined treatment by the histone deacetylase (HDAC) inhibitor TSA and the demethylating agent 5-aza-dc, as in our previous studies on Oct4 and Sox2. 24,30 Genomic DNA methylation and histone deacetylation are essential but not secluded epigeneticregulating mechanisms.…”

“…25,26 The QIAEX II kit (Qiagen, Hiden, Germany) was used for subsequent purification of converted DNA.…”

Hypermethylation of RASSF1A in Human and Rhesus Placentas

“…34,35 Xue and colleagues 34 reported the lack of hypermethylation in hypermethylated in cancer 1 (HIC1), TIMP metallopeptidase inhibitor 3 (TIMP3), cadherin 1, type 1, E-cadherin (CDH1), glutathione S-transferase pi (GSTP1), death-associated protein kinase 1 (DAPK1), and cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) (p16) in normal placentas. We have also studied the methylation status of .…”

p21-Activated Kinase-1 Promotes Aggressive Phenotype, Cell Proliferation, and Invasion in Gestational Trophoblastic Disease

“…31 Previous studies from our group and others have documented significantly reduced expression and hypermethylation of p16 in HMs and CCAs, particularly in patients who developed persistent GTN than those with spontaneous regression. 32,33 Aberrant methylation of p16 associated with its loss of expression in tumor cells have also been found in other tumors, including esophageal, colon, prostate, and pancreatic carcinomas, supporting the prominent tumor suppression role of p16. 31,34,35 The reciprocal expression pattern of PAK1 and p16 in GTD suggests that PAK1 is a putative upstream negative regulator of p16.…”