散发性结直肠癌CpG岛甲基子表型和基因组遗传学不稳定性的关系

目的探讨散发性结直肠癌CpG岛甲基子表型和基因组不稳定性的关系。方法对采用甲基化特异性PCR的方法对71例散发性结直肠癌组织进行P14^ARF、hMLH1、P16^INK4a、MGMT和MINT1共5个基因启动子甲基化的检测,确定CpG岛甲基子表型;选择BAT25和BAT26两个位点进行微卫星不稳定检测和流式细胞术检测分析倍体类型;分析散发性结直肠癌中CpG岛甲基子表型和微卫星不稳定、染色体不稳定的关系。结果全组结直肠癌组织中CpG岛甲基子表型的阳性率为21.1%（15/71）;微卫星不稳定的阳性率为9.9%（7/71）;异倍体的阳性率为73.5%（50/68）。CpG岛甲基子表型阳性者,微卫星不稳定的阳性率高于阴性者（20.0%vs7.1%）,但差异无统计学意义（P=0.158）。hMLH1基因启动子甲基化阳性者微卫星不稳定的比例为57.1%,高于阴性者的4.7%（P=0.001）。CpG岛甲基子表型阳性者二倍体的比例高于阴性者（61.5%vs.18.2%,P=0.003）。结论CpG岛甲基子表型阳性的散发性结直肠癌具有显著的二倍体倾向,多基因同时甲基化和染色体不稳定可能是两种相互独立的基础性发病机制。

Relationship between CpG island methylator phenotype and genetic instability in sporadic colorectal cancer

OBJECTIVE: To explore the relationship between CpG island methylator phenotype(CIMP) and genetic instability in sporadic colorectal cancer(SCRC). METHODS: Seventy-one SCRC patients were enrolled in this study. Promotor methylation status of five genes including P14(ARF ), hMLH1, P16(INK4a), MGMT and MINT1 was detected with methylation specific PCR to confirm CIMP. Microsatellite instability (MSI) status was evaluated with two microsatellite loci of BAT25 and BAT26, and the ploidy was detected with flow cytometry. The association between CIMP and MSI as well as chromosomal instability(CIN) was examined. RESULTS: The positive rates of CIMP, MSI and aneuploidy were 21.1% (15/71), 9.9% (7/71) and 73.5% (50/68) respectively. The positive rate of MSI in positive CIMP patients was higher than that in negative CIMP ones, but the difference was not significant (20.0% vs 7.1%,P=0.158). The positive rate of MSI was 57.1% in patients with hMLH1 gene promotor hypermethylation, which was significantly higher than that (4.7%) in patients without hMLH1 gene promotor hypermethylation (P=0.001). SCRCs with positive CIMP displayed significant inclination of diploidy (P=0.003). The positive rate of diploidy among SCRCs with CIMP was 61.5% while only 18.2% of cases without CIMP demonstrated diploid. CONCLUSIONS: SCRCs with positive CIMP are significantly more likely to be diploid. Simultaneous multiple genes hypermethylation represented by CIMP may be an epigenetic mechanism competing with the genetic mechanism of CIN.