Aberrant promoter hypermethylation and silencing of the critical 3p21 tumour suppressor gene, RASSF1A, in Chinese oesophageal squamous cell carcinoma
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 p...
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Veröffentlicht in: | International journal of oncology 2006-03, Vol.28 (3), p.767-773 |
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creator | LY WONG, Michelle QIAN TAO TSAO, George S. W LAM, King-Yin LAW, Simon WONG, John SRIVASTAVA, Gopesh LI FU WONG, Kai-Yau QIU, Guo-Hua LAW, Fian B. F TIN, Pui-Chi CHEUNG, Wai-Ling LEE, Ping-Yin TANG, Johnny Cheuk-On |
description | 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. |
doi_str_mv | 10.3892/ijo.28.3.767 |
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W ; LAM, King-Yin ; LAW, Simon ; WONG, John ; SRIVASTAVA, Gopesh ; LI FU ; WONG, Kai-Yau ; QIU, Guo-Hua ; LAW, Fian B. F ; TIN, Pui-Chi ; CHEUNG, Wai-Ling ; LEE, Ping-Yin ; TANG, Johnny Cheuk-On</creator><creatorcontrib>LY WONG, Michelle ; QIAN TAO ; TSAO, George S. W ; LAM, King-Yin ; LAW, Simon ; WONG, John ; SRIVASTAVA, Gopesh ; LI FU ; WONG, Kai-Yau ; QIU, Guo-Hua ; LAW, Fian B. F ; TIN, Pui-Chi ; CHEUNG, Wai-Ling ; LEE, Ping-Yin ; TANG, Johnny Cheuk-On</creatorcontrib><description>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.</description><identifier>ISSN: 1019-6439</identifier><identifier>EISSN: 1791-2423</identifier><identifier>DOI: 10.3892/ijo.28.3.767</identifier><identifier>PMID: 16465383</identifier><language>eng</language><publisher>Athens: Editorial Academy of the International Journal of Oncology</publisher><subject>Biological and medical sciences ; Carcinoma, Squamous Cell - epidemiology ; Carcinoma, Squamous Cell - genetics ; Carcinoma, Squamous Cell - pathology ; Cell Line, Tumor ; China - epidemiology ; Chromosomes, Human, Pair 3 - genetics ; DNA Methylation ; Esophageal Neoplasms - epidemiology ; Esophageal Neoplasms - genetics ; Esophageal Neoplasms - pathology ; Esophagus ; Gastroenterology. Liver. Pancreas. Abdomen ; Genes, Tumor Suppressor ; Humans ; Incidence ; Japan - epidemiology ; Medical sciences ; Neoplasm Staging ; Promoter Regions, Genetic - genetics ; Survival Analysis ; Tumor Suppressor Proteins - genetics ; Tumors</subject><ispartof>International journal of oncology, 2006-03, Vol.28 (3), p.767-773</ispartof><rights>2006 INIST-CNRS</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c388t-c71ff060f2db1a73ff5ef764f759883bb1d7ca090ca8e4cb2e6d56840ac940ce3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17493909$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16465383$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LY WONG, Michelle</creatorcontrib><creatorcontrib>QIAN TAO</creatorcontrib><creatorcontrib>TSAO, George S. W</creatorcontrib><creatorcontrib>LAM, King-Yin</creatorcontrib><creatorcontrib>LAW, Simon</creatorcontrib><creatorcontrib>WONG, John</creatorcontrib><creatorcontrib>SRIVASTAVA, Gopesh</creatorcontrib><creatorcontrib>LI FU</creatorcontrib><creatorcontrib>WONG, Kai-Yau</creatorcontrib><creatorcontrib>QIU, Guo-Hua</creatorcontrib><creatorcontrib>LAW, Fian B. F</creatorcontrib><creatorcontrib>TIN, Pui-Chi</creatorcontrib><creatorcontrib>CHEUNG, Wai-Ling</creatorcontrib><creatorcontrib>LEE, Ping-Yin</creatorcontrib><creatorcontrib>TANG, Johnny Cheuk-On</creatorcontrib><title>Aberrant promoter hypermethylation and silencing of the critical 3p21 tumour suppressor gene, RASSF1A, in Chinese oesophageal squamous cell carcinoma</title><title>International journal of oncology</title><addtitle>Int J Oncol</addtitle><description>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.</description><subject>Biological and medical sciences</subject><subject>Carcinoma, Squamous Cell - epidemiology</subject><subject>Carcinoma, Squamous Cell - genetics</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Cell Line, Tumor</subject><subject>China - epidemiology</subject><subject>Chromosomes, Human, Pair 3 - genetics</subject><subject>DNA Methylation</subject><subject>Esophageal Neoplasms - epidemiology</subject><subject>Esophageal Neoplasms - genetics</subject><subject>Esophageal Neoplasms - pathology</subject><subject>Esophagus</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Genes, Tumor Suppressor</subject><subject>Humans</subject><subject>Incidence</subject><subject>Japan - epidemiology</subject><subject>Medical sciences</subject><subject>Neoplasm Staging</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Survival Analysis</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumors</subject><issn>1019-6439</issn><issn>1791-2423</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1P3DAQhqOqqFDaW8-VL-1ps_VX_HFcraBFQkKC9hw5znhjlMTBdg77Q_i_GLESx548h2dez8xTVd8I3jKl6S__GLZUbdlWCvmhuiBSk5pyyj6WGhNdC870efU5pUeMadNg8qk6J4KLhil2UT3vOojRzBktMUwhQ0TDcYE4QR6Oo8k-zMjMPUp-hNn6-YCCQ3kAZKPP3poRsYUSlNcprBGldVkipBQiOsAMG3S_e3i4JrsN8jPaD36GBChACstgDlCa09NqSmdCFsYRWRPLF2EyX6ozZ8YEX0_vZfXv-urv_k99e_f7Zr-7rS1TKtdWEuewwI72HTGSOdeAk4I72WilWNeRXlqDNbZGAbcdBdE3QnFsrObYArusfr7lluWfVki5nXx6HcXMUKZqRQnjRIr_gkQr2VDFC7h5A20MKUVw7RL9ZOKxJbh99dUWXy1VLWuLr4J_P-Wu3QT9O3wSVIAfJ8Ckcm1XVFmf3jnJNdNYsxesIaDy</recordid><startdate>20060301</startdate><enddate>20060301</enddate><creator>LY WONG, Michelle</creator><creator>QIAN TAO</creator><creator>TSAO, George S. 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W</au><au>LAM, King-Yin</au><au>LAW, Simon</au><au>WONG, John</au><au>SRIVASTAVA, Gopesh</au><au>LI FU</au><au>WONG, Kai-Yau</au><au>QIU, Guo-Hua</au><au>LAW, Fian B. F</au><au>TIN, Pui-Chi</au><au>CHEUNG, Wai-Ling</au><au>LEE, Ping-Yin</au><au>TANG, Johnny Cheuk-On</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aberrant promoter hypermethylation and silencing of the critical 3p21 tumour suppressor gene, RASSF1A, in Chinese oesophageal squamous cell carcinoma</atitle><jtitle>International journal of oncology</jtitle><addtitle>Int J Oncol</addtitle><date>2006-03-01</date><risdate>2006</risdate><volume>28</volume><issue>3</issue><spage>767</spage><epage>773</epage><pages>767-773</pages><issn>1019-6439</issn><eissn>1791-2423</eissn><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.</abstract><cop>Athens</cop><pub>Editorial Academy of the International Journal of Oncology</pub><pmid>16465383</pmid><doi>10.3892/ijo.28.3.767</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Biological and medical sciences Carcinoma, Squamous Cell - epidemiology Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - pathology Cell Line, Tumor China - epidemiology Chromosomes, Human, Pair 3 - genetics DNA Methylation Esophageal Neoplasms - epidemiology Esophageal Neoplasms - genetics Esophageal Neoplasms - pathology Esophagus Gastroenterology. Liver. Pancreas. Abdomen Genes, Tumor Suppressor Humans Incidence Japan - epidemiology Medical sciences Neoplasm Staging Promoter Regions, Genetic - genetics Survival Analysis Tumor Suppressor Proteins - genetics Tumors |
title | Aberrant promoter hypermethylation and silencing of the critical 3p21 tumour suppressor gene, RASSF1A, in Chinese oesophageal squamous cell carcinoma |
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