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Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer

 Takeshi Nagasaka  ;  Minoru Koi  ;  Matthias Kloor  ;  Johannes Gebert  ;  Alex Vilkin  ;  Naoshi Nishida  ;  Sung Kwan Shin  ;  Hiromi Sasamoto  ;  Noriaki Tanaka  ;  Nagahide Matsubara  ;  C. Richard Boland  ;  Ajay Goel 
 GASTROENTEROLOGY, Vol.134(7) : 1950-1, 2008 
Journal Title
Issue Date
Aged ; Colon/enzymology ; Colorectal Neoplasms/enzymology ; Colorectal Neoplasms/genetics* ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms, Hereditary Nonpolyposis/enzymology ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; CpG Islands* ; DNA Methylation* ; Epigenesis, Genetic ; Female ; Gene Expression Regulation, Enzymologic* ; Gene Expression Regulation, Neoplastic* ; Genotype ; Germany ; Humans ; Japan ; Male ; Microsatellite Instability ; Middle Aged ; Mutation* ; Neoplasm Staging ; Phenotype ; Proto-Oncogene Proteins/genetics* ; Proto-Oncogene Proteins B-raf/genetics* ; Proto-Oncogene Proteins p21(ras) ; ras Proteins/genetics*
BRAF ; KRAS ; CIMP ; colon cancer ; methylation
BACKGROUND & AIMS: Colorectal cancers (CRCs) with the CpG island methylator phenotype (CIMP) often associate with epigenetic silencing of hMLH1 and an activating mutation in the BRAF gene. However, the current CIMP criteria are ambiguous and often result in an underestimation of CIMP frequencies in CRCs. Because BRAF and KRAS belong to same signaling pathway, we hypothesized that not only mutations in BRAF but mutant KRAS may also associate with CIMP in CRC. METHODS: We determined the methylation status in a panel of 14 markers (7 canonical CIMP-related loci and 7 new loci), microsatellite instability status, and BRAF/KRAS mutations in a collection of 487 colorectal tissues that included both sporadic and Lynch syndrome patients. RESULTS: Methylation analysis of 7 CIMP-related markers revealed that the mean number of methylated loci was highest in BRAF-mutated CRCs (3.6) vs KRAS-mutated (1.2, P < .0001) or BRAF/KRAS wild-type tumors (0.7, P < .0001). However, analyses with 7 additional markers showed that the mean number of methylated loci in BRAF mutant tumors (4.4) was the same as in KRAS mutant CRCs (4.3, P = .8610). Although sporadic microsatellite instability high tumors had the highest average number of methylated markers (8.4), surprisingly, Lynch syndrome CRCs also demonstrated frequent methylation (5.1). CONCLUSIONS: CIMP in CRC may result from activating mutations in either BRAF or KRAS, and the inclusion of additional methylation markers that correlate with mutant KRAS may help clarify CIMP in future studies. Additionally, aberrant DNA methylation is a common event not only in sporadic CRC but also in Lynch syndrome CRCs.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Shin, Sung Kwan(신성관) ORCID logo https://orcid.org/0000-0001-5466-1400
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