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Hypermethylation of the Ras Association Domain Family 1A (RASSF1A) Gene in Gallbladder Cancer  

Kee, Se Kook (Department of Surgery, Gumi CHA Hospital)
Lee, Ji Yun (Departments of Anatomy, Kyungpook National University)
Kim, Mi Jin (Departments of Anatomy, Kyungpook National University)
Lee, Su Man (Departments of Anatomy, Kyungpook National University)
Jung, Young Won (Departments of Anatomy, Kyungpook National University)
Kim, Young Joo (Departments of Internal Medicine, Kyungpook National University)
Park, Jae Yong (Departments of Internal Medicine, Kyungpook National University)
Bae, Han Ik (Departments of Pathology, Kyungpook National University)
Hong, Hae Sook (Department of Nursing, College of Nursing, Kyungpook National University)
Yun, Young Kook (Department of Surgery, School of Medicine Kyungpook National University)
Kim, Sang Geol (Department of Surgery, School of Medicine Kyungpook National University)
Kim, Dong Sun (Departments of Anatomy, Kyungpook National University)
Publication Information
Molecules and Cells / v.24, no.3, 2007 , pp. 364-371 More about this Journal
Abstract
The tumor suppressor gene Ras association domain family 1A (RASSF1A) is highly methylated in a wide range of human sporadic tumors. The current study investigated the hypermethylation of RASSF1A, the expression of RASSF1A protein, and the correlation between these and the clinicopathological features of gallbladder (GB) cancer in Korean patients. Formalin-fixed, paraffin-embedded tumors and non-neoplastic GB tissues (22 carcinomas, 8 adenomas, 26 normal epithelia) were collected from patients who had undergone surgical resection. The methylation status of two regions of the RASSF1A CpG island was determined by methylation-specific PCR (MSP), and the expression of RASSF1A protein was examined by immunohistochemistry using tissue microarrays. The K-RAS mutation was analyzed by direct sequencing. Methylation of the RASSF1A promoter (region 1) was detected in 22.7% (5/22) of carcinomas, 12.5% (1/8) of adenomas, and 0% (0/26) of normal gallbladder epithelia (P = 0.025). Methylation of the first exon (region 2) was found in 36.4% (8/22) of carcinomas, 25.0% (2/8) of adenomas, and 8.0% (2/26) of normal gallbladder epithelia (P = 0.038). K-RAS mutations were present in 4.5% (1/22) of carcinomas and 25% (2/8) of adenomas. RASSF1A methylaton was not associated with clinicopathological factors or K-ras mutation. Reduction or loss of RASSF1A expression was observed in most methylated adenocarcinomas. Three RASSF1A-expressing human biliary tract cancer cell lines examined contained unmethylated promoters and exons 1. These results suggest that downregulation of RASSF1A expression by DNA hypermethylation may be involved in GB carcinogenesis.
Keywords
CpG Island; Gallbladder Cancer; Hypermethylation; Immunohistochemistry; Methylation-specific PCR; RASSF1A;
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