Urothelial carcinomas arising in arsenic-contaminated areas are associated with hypermethylation of the gene promoter of the death-associated protein kinase.
OBJECTIVE
The mechanisms of urothelial carcinogenesis in areas highly contaminated with arsenic remain unclear. The aim was to determine whether hypermethylation of death-associated protein kinase (DAPK) gene is associated with chronic arsenic exposure.


RESULTS
The frequency of aberrant promoter methylation of DAPK in 17 urothelial carcinomas from an arsenic-contaminated area and 21 urothelial carcinomas from a non-arsenic-contaminated area was determined by methylation-specific polymerase chain reaction. DAPK hypermethylation status was significantly higher in urothelial cancers arising in arsenic-contaminated areas when compared with tumours from patients from non-contaminated areas (P = 0.018). In the subset of patients from living environments which were contaminated with arsenic, there was a statistically significant association between DAPK hypermethylation and patient's age, tumour invasiveness, histological grade and recurrence. This was not seen for urothelial carcinoma from patients from non-contaminated areas. A close correlation was also found between DAPK promoter methylation and low-intensity DAPK expression, as detected by immunohistochemistry (P = 0.037).


CONCLUSIONS
Exposure to arsenic may induce DAPK promoter hypermethylation and inactivate the function of DAPK in urothelial carcinoma. This could prove to be a key molecular event contributing to the malignant phenotype of tumour arising in patients from arsenic-contaminated environments.
Chen
W-T
WT
Department of Pathology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan.
Hung
W-C
WC
Kang
W-Y
WY
Huang
Y-C
YC
Chai
C-Y
CY
D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D020261:Arsenic Poisoning / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics*; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D013624:Taiwan / Q000453:epidemiology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics*; D019459:Urothelium / Q000187:drug effects / Q000473:pathology
D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases