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Molecular cytogenetic, epigenetic and tissue dynamic study of gestational trophoblastic disease

by Xue, Weicheng

Abstract (Summary)
(Uncorrected OCR) Abstract of thesis entitled Molecular cytogenetic, epigenetic and tissue dynamic study of gestational trophoblastic disease submitted by XUE Wei Cheng for the degree of Doctor of Philosophy at the University of Hong Kong in August, 2004 Gestational trophoblastic disease (GTD) encompasses a heterogeneous group of lesions characterized by abnormal proliferation of trophoblast including hydatidiform mole (HM), invasive mole, choriocarcinoma, placenta site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor. The latter three are true neoplasms, whereas HM, which can be subclassified into complete (CHM) and partial mole (PHM), represents abnormal placenta prone to neoplastic transformation. Approximately 8-30% of molar pregnancies will develop gestational trophoblastic neoplasia (GTN) requiring chemotherapy. Identification of reliable and specific markers predicting the behavior of HM is of special clinical significance. In this thesis, comprehensive studies have been conducted to better understand the biological, genetic and epigenetic changes associated with the genesis and progression of GTD. Special interest has been focused on HM because of its mysterious pathogenesis and unpredictable clinical course. Chromosome in situ hybridization (CISH) and microsatellite genotyping analysis have been found helpful to refine the classification of 51 cases of HM, especially in cases with difficult histological evaluation. The histological diagnosis was more accurate in CHM (91%, 31/34). Most originally diagnosed metastatic PHMs (67%, 4/6) were actually CHMs. Two rare cases of metastatic PSTTs were successfully analyzed by comparative genomic hybridization and CISH. Balanced diploid karyotype was demonstrated. Differential expression of cadherin profiles in 12 normal placentas and 32 HMs and five choriocarcinomas was analyzed by immunohistochemistry, western blot, and semiquantitative RT-PCR. E-cadherin was mainly expressed in cytotrophoblast whereas cadherin-11 in syncytiotrophoblast. Compared with normal placenta, expression of E-cadherin was reduced in HM and choriocarcinoma (P=0.04, P<0.01) while cadherin-11 was higher in HM (P=0.02), but lower in choriocarcinoma (P=0.02). No obvious association was observed between expression of cadherins and development of GTN. Promoter methylation of six genes was investigated in 54 HMs and five choriocarcinomas by methylation-specific PCR. Four genes (E-cadherin, FflC-1, pi6, TIMP3) in choriocarcinoma and three genes (E-cadherin, HIC-1, pi6) in HM exhibited aberrant methylation whereas no hypermethylation of either DAPK or GSTP1 genes were demonstrated in all the GTD cases. There was a significant correlation between methylation and reduced expression of pi6, E-cadherin, and TIMP3 (PO.001). Promoter hypermethylation of pl6 alone (P=0.001), or combined with E-cadherin (P<0.0005), was significantly correlated with the development of GTN. Differential expression of a novel proliferation marker minichromosome maintenance protein 7 (MCM7), a meiosis related gene c-mos, and four Id proteins (Idl-Id4) were investigated in 122 trophoblastic tissues by immunohistochemistry. Immunoreactivity of MCM7 or Idl, which predominantly expressed in proliferating cells, was significantly higher in molar than in non-molar gestations (P=0.007, P=0.0001) but was not helpful in predicting GTN (P=0.312, P=0.454). C-mos staining was positive in all 45 HMs and 17 choriocarcinomas but negative in all 5 PSTTs, 26 germ cell tumors and 66 gynecological non-trophoblastic tumors, thus could be an adjuvant in differential diagnosis. In conclusion, application of a wide range of laboratory techniques improves the histological diagnosis and helps in understanding the pathogenesis and progression of the GTD. In particular, hypermethylation of pl6 gene was found to be a good potential prognostic candidate deserving further study. An abstract of 495 words
Bibliographical Information:

Advisor:

School:The University of Hong Kong

School Location:China - Hong Kong SAR

Source Type:Master's Thesis

Keywords:trophoblastic tumors genetic aspects

ISBN:

Date of Publication:01/01/2005

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