Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis

Masanori Takeda, Takeshi Nagasaka, Sun Dong-Sheng, Hiroyuki Nishie, Tetsuhiro Oka, Eiji Yamada, Yoshiko Mori, Kunitoshi Shigeyasu, Tatsuya Morikawa, Satoshi Mizobuchi, Toshiyoshi Fujiwara

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27 Citations (Scopus)


Secreted frizsled-related protein 2, (SFRP2) is a Wnt inhibitor whose promoter CpGs were recently found to be methylated at high frequency in colorectal cancers (CRCs). We hypothesized that the pattern of SFRP2 methylation may differ throughout the promoter during progressive tumorigenesis. Using combined bisulfite restriction analysis (COBRA), two methylation-sensitive regions (Regions A and B) of the SFRP2 promoter were investigated in 569 specimens of colorectal tissue: 222 CRCs, 103 adenomatous polyps (APs), 208 normal colonic mucosa from CRC patients (N-Cs), and 36 normal colonic mucosa from subjects with no evidence of colorectal neoplasia at colonoscopy (N-Ns). Extensive (including both Regions A and B) and partial (either Region A or B) SFRP2 methylation levels were found in 61.7% and 24.8% of CRCs, 8.7% and 37.9% of APs, 3.9% and 39.9% of N-Cs, and 0% and 30.6% of N-Ns, respectively. Extensive methylation of the SFRP2 promoter was present primarily in CRCs, while partial methylation was common in APs. Whereas APs with the KRAS mutant showed no correlation to any pattern of SFRP2 methylation, extensive methylation of the SFRP2 promoter was significantly associated with KRAS mutant CRCs (p < .0001), suggesting that genetic alteration in the RAS-RAF pathway might precede the spread of CpG methylation through the SFRP2 promoter, which is observed in over 60% of advanced colorectal tumors.

Original languageEnglish
Pages (from-to)169-177
Number of pages9
JournalActa medica Okayama
Issue number3
Publication statusPublished - Jun 2011


  • BRAF/KRAS mutations
  • Colorectal cancer
  • Promoter methylation

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology


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