Frequent promoter methylation of CDH1, DAPK, RARB, and HIC1 genes in carcinoma of cervix uteri: its relationship to clinical outcome.
BACKGROUND
Cervical cancer (CC), a leading cause of cancer-related deaths in women worldwide, has been causally linked to genital human papillomavirus (HPV) infection. Although a host of genetic alterations have been identified, molecular basis of CC development is still poorly understood.


RESULTS
We examined the role of promoter hypermethylation, an epigenetic alteration that is associated with the silencing tumor suppressor genes in human cancer, by studying 16 gene promoters in 90 CC cases. We found a high frequency of promoter methylation in CDH1, DAPK, RARB, and HIC1 genes. Correlation of promoter methylation with clinical characteristics and other genetic changes revealed the following: a) overall promoter methylation was higher in more advanced stage of the disease, b) promoter methylation of RARB and BRCA1 predicted worse prognosis, and c) the HIC1 promoter methylation was frequently seen in association with microsatellite instability. Promoter methylation was associated with gene silencing in CC cell lines. Treatment with methylation or histone deacetylation-inhibiting agents resulted in profound reactivation of gene expression.


CONCLUSIONS
These results may have implications in understanding the underlying epigenetic mechanisms in CC development, provide prognostic indicators, and identify important gene targets for treatment.
Narayan
Gopeshwar
G
Department of Pathology, Columbia University, New York, New York 10032, USA. gn110@columbia.edu
Arias-Pulido
Hugo
H
Koul
Sanjay
S
Vargas
Hernan
H
Zhang
Fang F
FF
Villella
Jeannine
J
Schneider
Achim
A
Terry
Mary B
MB
Mansukhani
Mahesh
M
Murty
Vundavalli V
VV
D051017:Apoptosis Regulatory Proteins; D015820:Cadherins / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D018895:Microsatellite Repeats; D027383:Papillomaviridae / Q000302:isolation & purification; D011379:Prognosis; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D015820:Cadherins; C096870:Hic1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; C082925:retinoic acid receptor beta; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases