title: Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis.
abstract: Secreted frizzled-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.
authors.affiliation: Department of Gastroenterological Surgery and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Takeda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Sun
authors.initials: S
authors.lastname: Dong-Sheng
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishie
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Oka
authors.forename: Eiji
authors.initials: E
authors.lastname: Yamada
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Mori
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Shigeyasu
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Morikawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mizobuchi
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000368:Aged; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism*; D018899:CpG Islands / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D008565:Membrane Proteins; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins