Brandes Johann C, van Engeland Manon, Wouters Kim A D, Weijenberg Matty P, Herman James G
Cancer Biology Program, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Carcinogenesis. 2005 Jun;26(6):1152-6. doi: 10.1093/carcin/bgi058. Epub 2005 Mar 10.
A subset of sporadic colon cancers has been shown to have microsatellite instability caused by an epigenetic inactivation of the MLH1 gene by hypermethylation of the the CpG island in its promoter region. We report here that in colorectal cancer, inactivation of the MLH1 gene is frequently accompanied by hypermethylation of the CpG island in the promoter of the mitotic gene checkpoint with forkhead and ring finger domains (CHFR). This was first observed in the colon cancer cell lines HCT-116, DLD-1, RKO and HT29. Among the 61 primary colon cancer samples studied, hypermethylation of the MLH1 and the CHFR promoter was found in 31% of the tumors. In 68% of all primary cancers (13/19) with MLH1 promoter hypermethylation, hypermethylation of the CHFR promoter was observed as well (P-value < 0.0001, Fisher's two-sided exact). Hypermethylation of the HLTF, MGMT, RASSF1, APC, p14 and p16 promoter regions were also frequent events, being observed in 48% (28/58), 40% (26/64), 21% (14/64), 50% (31/62), 43% (26/60) and 56% (35/63), respectively. However, methylation of these genes was not associated with methylation of either MLH1 or CHFR. The observed methylation profile was unrelated to Duke's stage. The coordinated loss of both mismatch repair caused by methylation of MLH1 and loss of checkpoint control associated with methylation of CHFR suggests the potential to overcome cell cycle checkpoints, which may lead to an accumulation of mutations.
已显示一部分散发性结肠癌存在微卫星不稳定性，这是由其启动子区域CpG岛的高甲基化导致MLH1基因发生表观遗传失活所致。我们在此报告，在结直肠癌中，MLH1基因的失活常伴随着有叉头和环指结构域的有丝分裂基因检查点（CHFR）启动子中CpG岛的高甲基化。这一现象首先在结肠癌细胞系HCT-116、DLD-1、RKO和HT29中被观察到。在所研究的61个原发性结肠癌样本中，31%的肿瘤中发现了MLH1和CHFR启动子的高甲基化。在所有MLH1启动子高甲基化的原发性癌症（13/19）中，68%也观察到了CHFR启动子的高甲基化（P值<0.0001，Fisher双侧精确检验）。HLTF、MGMT、RASSF1、APC、p14和p16启动子区域的高甲基化也是常见事件，分别在48%（28/58）、40%（26/64）、21%（14/64）、50%（31/62）、43%（26/60）和56%（35/63）的样本中被观察到。然而，这些基因的甲基化与MLH1或CHFR的甲基化均无关联。观察到的甲基化谱与杜克分期无关。由MLH1甲基化导致的错配修复功能丧失以及与CHFR甲基化相关的检查点控制丧失，提示可能存在克服细胞周期检查点的潜力，这可能导致突变的积累。
