Konishi Kazuo, Shen Lanlan, Wang Suna, Meltzer Stephen J, Harpaz Noam, Issa Jean-Pierre J
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Gastroenterology. 2007 Apr;132(4):1254-60. doi: 10.1053/j.gastro.2007.01.035. Epub 2007 Jan 25.
BACKGROUND & AIMS: We previously reported that a high degree of age-related methylation was found in both the dysplastic and nondysplastic mucosa of patients with ulcerative colitis (UC). Whether this translates into hypermethylation in UC-associated cancers (UC-Cs) is not known.
We evaluated the methylation status of 11 genes (MINT1, 2, 31, hMLH1, p16, p14, MGMT, HPP1, SFRP1, ERalpha, and LINE-1) in 48 UC-Cs, 21 UC-associated dysplasias, and 69 sporadic colorectal cancers (S-CRCs) using a quantitative bisulfite pyrosequencing analysis.
Methylation levels in UC-Cs were lower than S-CRCs for all the genes except MGMT. A methylation index based on the average of Z-scores, for type C (cancer-specific genes: MINT1, MINT2, MINT31, hMLH1, p16, and p14) was -.97 in UC-Cs and .92 in S-CRCs (P = .009). That of type A (age-related genes: HPP1, SFRP1, and ERalpha) was -1.97 in UC-Cs and 1.24 in S-CRCs (P < .001). We observed a significant difference in the incidence of CpG island methylator phenotype between UC-Cs and S-CRCs (8 of 48 [17%] and 26 of 69 [38%]; P = .022). UC-associated dysplasias had significantly higher methylation of type A gene than UC-Cs (Z-score: .07 and -1.97, respectively; P < .001). By contrast, global DNA methylation measured using a LINE-1 assay was significantly higher in UC-Cs than in S-CRCs (58.2% vs 51.0%, P < .001).
DNA methylation alterations are uncommon in UC cancers. Given that both genetic and epigenetic changes are common in UC mucosa and dysplasias, we speculate that the genetic changes lead to a more aggressive clinical course than epigenetic changes.
我们之前报道过，在溃疡性结肠炎（UC）患者的发育异常和未发育异常的黏膜中均发现了高度的年龄相关甲基化。目前尚不清楚这是否会转化为UC相关癌症（UC-C）中的高甲基化。
我们使用定量亚硫酸氢盐焦磷酸测序分析评估了48例UC-C、21例UC相关发育异常和69例散发性结直肠癌（S-CRC）中11个基因（MINT1、2、31、hMLH1、p16、p14、MGMT、HPP1、SFRP1、ERα和LINE-1）的甲基化状态。
除MGMT外，UC-C中所有基因的甲基化水平均低于S-CRC。基于Z分数平均值的甲基化指数，C型（癌症特异性基因：MINT1、MINT2、MINT31、hMLH1、p16和p14）在UC-C中为-.97，在S-CRC中为.92（P = .009）。A型（年龄相关基因：HPP1、SFRP1和ERα）在UC-C中为-1.97，在S-CRC中为1.24（P < .001）。我们观察到UC-C和S-CRC之间CpG岛甲基化表型的发生率存在显著差异（48例中的8例[17%]和69例中的26例[38%]；P = .022）。UC相关发育异常中A型基因的甲基化显著高于UC-C（Z分数分别为.07和-1.97；P < .001）。相比之下，使用LINE-1检测法测得的全基因组DNA甲基化在UC-C中显著高于S-CRC（58.2%对51.0%，P < .001）。
DNA甲基化改变在UC癌症中并不常见。鉴于UC黏膜和发育异常中遗传和表观遗传变化均很常见，我们推测遗传变化比表观遗传变化导致更具侵袭性的临床病程。
