AIMS: 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. METHODS AND 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). CONCLUSION: 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.
AIMS: 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. METHODS AND 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). CONCLUSION: 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.
Authors: L J Melchers; M J A M Clausen; M F Mastik; L Slagter-Menkema; J E van der Wal; G B A Wisman; J L N Roodenburg; E Schuuring Journal: Epigenetics Date: 2015 Impact factor: 4.528
Authors: Angeliki Lambrou; Andrea Baccarelli; Robert O Wright; Marc Weisskopf; Valentina Bollati; Chitra Amarasiriwardena; Pantel Vokonas; Joel Schwartz Journal: Epidemiology Date: 2012-09 Impact factor: 4.822