Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis.
Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis.
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DOI：
10.18926/amo/46628
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发表时间：
2011-06
影响因子：
0.5
通讯作者：
Masanori Takeda;T. Nagasaka;Sun Dong-sheng;Hiroyuki Nishie;T. Oka;E. Yamada;Y. Mori;K. Shigeyasu;T. Morikawa;S. Mizobuchi;T. Fujiwara
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文献类型：
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作者：
Masanori Takeda;T. Nagasaka;Sun Dong-sheng;Hiroyuki Nishie;T. Oka;E. Yamada;Y. Mori;K. Shigeyasu;T. Morikawa;S. Mizobuchi;T. Fujiwara
分泌型卷曲相关蛋白2（SFRP 2）是一种Wnt抑制剂，其启动子CpG最近被发现在结直肠癌（CRC）中以高频率甲基化。我们推测，在进行性肿瘤发生过程中，SFRP 2甲基化的模式可能在整个启动子中有所不同。使用联合亚硫酸氢盐限制性分析（COBRA），在569个结直肠组织标本中研究了SFRP 2启动子的两个甲基化敏感区域（区域A和B）：222个CRC、103个腺瘤性息肉（AP）、208个来自CRC患者的正常结肠粘膜（N-Cs）和36个来自结肠镜检查时没有结直肠肿瘤证据的受试者的正常结肠粘膜（N-Ns）。广泛（包括区域A和B）和部分（区域A或B）SFRP 2甲基化水平分别见于61.7%和24.8%的CRC、8.7%和37.9%的AP、3.9%和39.9%的N-Cs以及0%和30.6%的N-Ns。SFRP 2启动子的广泛甲基化主要存在于CRC中，而部分甲基化在AP中很常见。尽管KRAS突变的AP与SFRP 2甲基化的任何模式都没有相关性，但SFRP 2启动子的广泛甲基化与KRAS突变的CRC显著相关（p<.0001），表明RAS-RAF途径中的遗传改变可能先于CpG甲基化通过SFRP 2启动子的扩散，这在超过60%的晚期结直肠肿瘤中观察到。
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.