Aberrant promoter hypermethylation and silencing of the critical 3p21 tumour suppressor gene, RASSF1A, in Chinese oesophageal squamous cell carcinoma

Michelle L.Y. Wong, Qian Tao, L. I. Fu, Kai Yau Wong, Guo Hua Qiu, Fian B.F. Law, Pui Chi Tin, Wai Ling Cheung, Ping Yin Lee, Cheuk On Tang, George S.W. Tsao, King Yin Lam, Simon Law, John Wong, Gopesh Srivastava

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44 Citations (Scopus)

Abstract

3p21 is an important locus harbouring critical tumour suppressor genes (TSG), which are implicated in the pathogenesis of multiple tumours, including oesophageal carcinoma. RASSF1A is a 3p21.3 candidate TSG frequently inactivated by promoter methylation in multiple tumours. We investigated RASSF1A promoter methylation and gene expression in Chinese oesophageal squamous cell carcinoma (ESCC) to compare it to data from Japanese patients. Methylation-specific PCR (MSP) showed that RASSF1A was partially methylated in 3/7 (43%) cell lines; 22/64 (34%) primary tumours and 3/64 (5%) corresponding non-tumour samples; and was not methylated in 2 immortalized normal oesophageal epithelial cell lines and 6 normal oesophageal epithelium samples. Bisulfite genome sequencing confirmed the MSP results. Promoter hypermethylation correlated well with RASSF1A mRNA down-regulation. Treatment of cell lines with 5-aza-2′- deoxycytidine activated RASSF1A mRNA expression along with promoter demethylation. RASSF1A hypermethylation in the Chinese cohort was much lower than in a published report of Japanese ESCC patients (52%) and cell lines (74%). Our own analysis of Japanese ESCC cell lines for direct comparison also detected a high frequency of RASSF1A hypermethylation (8/10; 80%) and high levels of hypermethylation at each CpG site. No significant association between RASSF1A hypermethylation and histological differentiation (p=0.953), tumour staging (p=0.117), or survival (p=0.7571) was found in Chinese ESCC, unlike the results of Japanese patients. The incidence of oesophageal cancer shows marked variation by geographic area and ethnic group; it is almost three times higher in China than in Japan, indicating possible different pathogenetic mechanisms. Our results show that RASSF1A hypermethylation in ESCC has epidemiological/ ethnic differences, and suggest that Chinese ESCC may result from different pathogenetic mechanisms.
Original languageEnglish
Pages (from-to)767-773
Number of pages7
JournalInternational Journal of Oncology
Volume28
Issue number3
Publication statusPublished - 1 Mar 2006

Keywords

  • 3p21
  • Methylation
  • Oesophageal carcinoma
  • RASSF1A
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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