Barault Ludovic, Charon-Barra Céline, Jooste Valérie, de la Vega Mathilde Funes, Martin Laurent, Roignot Patrick, Rat Patrick, Bouvier Anne-Marie, Laurent-Puig Pierre, Faivre Jean, Chapusot Caroline, Piard Francoise
Service d'Anatomie Pathologique, Institut National de la Sante et de la Recherche Medicale, Université de Bourgogne, Dijon, France.
Cancer Res. 2008 Oct 15;68(20):8541-6. doi: 10.1158/0008-5472.CAN-08-1171.
The CpG island methylator phenotype (CIMP) is a distinct phenotype in colorectal cancer, associated with specific clinical, pathologic, and molecular features. However, most of the studies stratified methylation according to two subgroups (CIMP-High versus No-CIMP/CIMP-Low). In our study, we defined three different subgroups of methylation (No-CIMP, CIMP-Low, and CIMP-High) and evaluated the prognostic significance of methylation status on a population-based series of sporadic colon cancers. A total of 582 colon adenocarcinomas were evaluated using methylation-specific PCR for 5 markers (hMLH1, P16, MINT1, MINT2, and MINT31). No-CIMP status was defined as no methylated locus, CIMP-Low status as one to three methylated loci, and CIMP-High status as four or five methylated loci. Clinicopathologic and molecular characteristics were correlated to the methylation status. Crude and relative survival was compared according to methylation status. In the microsatellite-stable (MSS) group, CIMP-High was significantly associated with proximal location (P = 0.011) and BRAF mutation (P < 0.001). KRAS mutations were more associated with CIMP-High and CIMP-Low status (P = 0.008). A shorter 5-year survival was observed in MSS cancer patients with CIMP-Low or CIMP-High status. These results remained significant in multivariate analysis adjusted for age, stage, and BRAF and KRAS mutational status [CIMP-Low: hazard ratio (HR), 1.85; 95% confidence interval (95% CI), 1.37-2.51; CIMP-High, HR, 2.90; 95% CI, 1.53-5.49 compared with No-CIMP]. Within the high-level microsatellite instability group, no difference in survival was observed between the different CIMP groups. Our results show the interest of defining three subgroups of patients according to their methylation status (No-CIMP/CIMP-Low/CIMP-High). Methylation is an independent prognostic factor in MSS colon cancer.
CpG岛甲基化表型（CIMP）是结直肠癌中一种独特的表型，与特定的临床、病理和分子特征相关。然而，大多数研究根据两个亚组（CIMP高甲基化与非CIMP/低甲基化）对甲基化进行分层。在我们的研究中，我们定义了三个不同的甲基化亚组（非CIMP、低甲基化CIMP和高甲基化CIMP），并在基于人群的散发性结肠癌系列中评估了甲基化状态的预后意义。使用甲基化特异性PCR对5个标志物（hMLH1、P16、MINT1、MINT2和MINT31）对总共582例结肠腺癌进行了评估。非CIMP状态定义为无甲基化位点，低甲基化CIMP状态定义为1至3个甲基化位点，高甲基化CIMP状态定义为4或5个甲基化位点。将临床病理和分子特征与甲基化状态相关联。根据甲基化状态比较了粗生存率和相对生存率。在微卫星稳定（MSS）组中，高甲基化CIMP与近端位置（P = 0.011）和BRAF突变（P < 0.001）显著相关。KRAS突变与高甲基化CIMP和低甲基化CIMP状态更相关（P = 0.008）。在低甲基化CIMP或高甲基化CIMP状态的MSS癌症患者中观察到5年生存率较短。在针对年龄、分期以及BRAF和KRAS突变状态进行调整的多变量分析中，这些结果仍然显著[低甲基化CIMP：风险比（HR），1.85；95%置信区间（95%CI），1.37 - 2.51；高甲基化CIMP，HR，2.90；95%CI，1.53 - 5.49，与非CIMP相比]。在高度微卫星不稳定组中，不同CIMP组之间未观察到生存率差异。我们的结果表明，根据患者的甲基化状态（非CIMP/低甲基化CIMP/高甲基化CIMP）定义三个亚组具有重要意义。甲基化是MSS结肠癌的一个独立预后因素。
