Cyclin A1 promoter hypermethylation in human papillomavirus-associated cervical cancer.
BACKGROUND
The aim of this study was to evaluate epigenetic status of cyclin A1 in human papillomavirus-associated cervical cancer. Y. Tokumaru et al., Cancer Res 64, 5982-7 (Sep 1, 2004)demonstrated in head and neck squamous-cell cancer an inverse correlation between cyclin A1 promoter hypermethylation and TP53 mutation. Human papillomavirus-associated cervical cancer, however, is deprived of TP53 function by a different mechanism. Therefore, it was of interest to investigate the epigenetic alterations during multistep cervical cancer development.


METHODS
In this study, we performed duplex methylation-specific PCR and reverse transcriptase PCR on several cervical cancer cell lines and microdissected cervical cancers. Furthermore, the incidence of cyclin A1 methylation was studied in 43 samples of white blood cells, 25 normal cervices, and 24, 5 and 30 human papillomavirus-associated premalignant, microinvasive and invasive cervical lesions, respectively.


RESULTS
We demonstrated cyclin A1 methylation to be commonly found in cervical cancer, both in vitro and in vivo, with its physiological role being to decrease gene expression. More important, this study demonstrated that not only is cyclin A1 promoter hypermethylation strikingly common in cervical cancer, but is also specific to the invasive phenotype in comparison with other histopathological stages during multistep carcinogenesis. None of the normal cells and low-grade squamous intraepithelial lesions exhibited methylation. In contrast, 36.6%, 60% and 93.3% of high-grade squamous intraepithelial lesions, microinvasive and invasive cancers, respectively, showed methylation.


CONCLUSIONS
This methylation study indicated that cyclin A1 is a potential tumor marker for early diagnosis of invasive cervical cancer.
Kitkumthorn
Nakarin
N
Molecular Biology and Genetics of Cancer Development Research Unit, Faculty of Medicine, Chulalongkorn University, Rama IV., Bangkok 10330, Thailand. Art_khuan@hotmail.com
Yanatatsanajit
Pattamawadee
P
Kiatpongsan
Sorapop
S
Phokaew
Chureerat
C
Triratanachat
Surang
S
Trivijitsilp
Prasert
P
Termrungruanglert
Wichai
W
Tresukosol
Damrong
D
Niruthisard
Somchai
S
Mutirangura
Apiwat
A
D014408:Biomarkers, Tumor / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000821:virology*; D002471:Cell Transformation, Neoplastic; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism*; D056750:Cyclin A1; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D027383:Papillomaviridae / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000150:complications*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000473:pathology
D014408:Biomarkers, Tumor; C503745:CCNA1 protein, human; D019925:Cyclin A; D056750:Cyclin A1