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RASSF1A hypermethylation and its inverse correlation with BRAF and/or KRAS mutations in MSI-associated endometrial carcinoma

 Sokbom Kang  ;  Jae Myun Lee  ;  Eun-Sook Jeon  ;  Sun Lee  ;  Hogeun Kim  ;  Hy-Sook Kim  ;  Sang-Soo Seo  ;  Sang-Yoon Park  ;  David Sidransky  ;  Seung Myung Dong 
 International Journal of Cancer, Vol.119(6) : 1316-1321, 2006 
Journal Title
 International Journal of Cancer 
Issue Date
DNA Methylation* ; DNA Mutational Analysis ; Endometrial Neoplasms/genetics* ; Endometrial Neoplasms/pathology ; Female ; Genes, ras/genetics* ; Genetic Predisposition to Disease ; Humans ; Microsatellite Repeats* ; Mutation/genetics* ; Neoplasm Proteins/genetics ; Promoter Regions, Genetic ; Proto-Oncogene Proteins B-raf/genetics* ; Tumor Suppressor Proteins/genetics*
RASSF1A promoter hypermethylation ; BRAF ; KRAS ; endometrial carcinoma ; hMLH1 ; MSI
Both hypermethylation of the tumor suppressor gene RASSF1A and activating mutations of the KRAS and/or BRAF gene have been reported in a variety of human cancers. To investigate these epigenetic and genetic alterations in endometrial carcinoma (EC), we examined their frequency in 4 uterine EC cell lines and in 75 sporadic primary ECs. Using methylation specific PCR, we found RASSF1A methylation in 25 of 75 (33.3%) ECs. RASSF1A methylation was significantly associated with microsatellite instability (MSI, p < 0.001) and also with hMLH1 methylation (p < 0.001). KRAS mutations were detected in 14 of 75 (18.7%) ECs. BRAF mutations were identified in only 3 of 75 (4.0%) ECs and were not found in ECs with KRAS mutations or RASSF1A methylation. RASSF1A methylation was more frequent in KRAS mutation-negative ECs than in KRAS mutation-positive ECs (37.7% vs 14.3%), but this inverse correlation is not statistically significant (p = 0.122). However, we observed that RASSF1A methylation was inversely correlated with KRAS and/or BRAF mutations (p = 0.028) in MSI-negative ECs, while this inverse correlation disappeared in MSI-positive ECs. Furthermore, in MSI-positive ECs, 2 cases of concomitant RASSF1A methylation and KRAS mutation were found. Taken together, these results provide strong evidence that, in EC tumorigenesis, RASSF1A promoter hypermethylation is as important as KRAS mutations in activating the RAS pathway.
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1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Ho Keun(김호근)
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
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