Hypermethylation of RAS effector related genes and DNA methyltransferase 1 expression in endometrial carcinogenesis.
Epigenetic aberration is known to be important in human carcinogenesis. Promoter methylation status of RAS effector related genes, RASSF1A, RASSF2A, hDAB2IP (m2a and m2b regions) and BLU, was evaluated in 76 endometrial carcinomas and their non-neoplastic endometrial tissue by methylation specific PCR. Hypermethylation of at least one of the 5 genes was detected in 73.7% of carcinomas. There were significant correlations between methylation of hDAB2IP and RASSF1A, RASSF2A (p = 0.042, p = 0.012, respectively). Significantly, more frequent RASSF1A hypermethylation was found in Type I endometrioid carcinomas than Type II carcinomas (p = 0.049). Among endometrioid cancers, significant association between RASSF1A hypermethylation and advanced stage, as well as between methylation of hDAB2IP at m2a region with deep myometrial invasion (p < 0.05) was observed. mRNA expression of RASSF1A, RASSF2A and BLU in endometrial cancer cell lines significantly increased after treatment with the demethylating agent 5-Aza-2'-deoxycytidine supporting the repressive effect of hypermethylation on their transcription. Immunohistochemical study of DNMT1 on eight normal endometrium, 16 hyperplastic endometrium without atypia, 40 atypical complex hyperplasia and 79 endometrial carcinomas showed progressive increase in DNMT1 immunoreactivity from normal endometrium to endometrial hyperplasia and endometrioid carcinomas (p = 0.001). Among carcinomas, distinctly higher DNMT1 expression was observed in Type I endometrioid carcinomas (p < 0.001). DNMT1 immunoreactivity correlated with RASSF1A and RASSF2A methylation (p < 0.05). The data suggested that hypermethylation of RAS related genes, particularly RASSF1A, was involved in endometrial carcinogenesis with possible divergent patterns in different histological types. DNMT1 protein overexpression might contribute to such aberrant DNA hypermethylation of specific tumor suppressor genes in endometrial cancers.
Liao
Xiaoyun
X
Department of Pathology, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong.|Department of Pathology, Peking University People's Hospital, Beijing, China.
Siu
Michelle Kwan-Yee
MK
Department of Pathology, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong.
Chan
Kelvin Yuen-Kwong
KY
Department of Pathology, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong.
Wong
Esther Shuk-Ying
ES
Department of Pathology, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong.
Ngan
Hextan Yuen-Sheung
HY
Department of Obstetrics and Gynaecology, the University of Hong Kong, Pokfulam Road, Hong Kong, China.
Chan
Queeny Kwan-Yi
QK
Department of Pathology, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong.
Li
Albert Siu-Ming
AS
Department of Pathology, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong.
Khoo
Ui-Soon
US
Department of Pathology, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong.
Cheung
Annie Nga-Yin
AN
Department of Pathology, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins; D019175:DNA Methylation; D017931:DNA Primers; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
D003598:Cytoskeletal Proteins; C462952:DAB2IP protein, human; C411744:DMAP1 protein, human; D017931:DNA Primers; D011506:Proteins; C411762:RASSF1 protein, human; C425300:RASSF2 protein, human; D012333:RNA, Messenger; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C472720:ZMYND10 protein, human; D020703:ras GTPase-Activating Proteins