Royal Brisbane and Women's Hospital Research Foundation Clinical Research Centre, Brisbane, Queensland, Australia.
Oncogene. 2010 Mar 18;29(11):1653-62. doi: 10.1038/onc.2009.449. Epub 2009 Dec 7.
There are two major molecular pathways to sporadic colorectal cancer, the chromosomal instability (CIN) and the CpG island methylator phenotype (CIMP) pathways. This study recruited 166 patients undergoing colonoscopy. Biopsy samples were collected from the cecum, transverse colon, sigmoid colon and rectum. DNA methylation was quantified at 'type A' (ESR1, GATA5, HIC1, HPP1, SFRP1) and 'type C' markers (MGMT, MLH1, CDKN2A, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. 'Type A' genes are frequently methylated in normal and neoplastic tissues, proportional to tissue age. 'Type C' methylation is more specific for neoplasia. The last five 'type C' markers comprise a CIMP panel. The mean 'type A' and CIMP-panel methylation Z-scores were calculated. In all, 88 patients had adenomatous lesions, 32 had proximal serrated polyps (PSPs) and 50 were normal. Most 'type A' genes showed direct correlations between methylation and age (ESR1, rho=0.66, P<0.0001), with higher methylation distally (ESR1, P<0.0001). On multivariate analysis, 'type A' methylation was inversely associated with colorectal adenomas (odds ratio=0.23, P<0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio=5.1, P=0.009), the precursor to CIMP cancers. DNA methylation in normal mucosa varied with age and region and was associated with pathway-specific pathology. In the future, the colorectal field could yield important information and potentially inform clinical practice.
结直肠癌的发生存在两种主要的分子途径，即染色体不稳定性（CIN）途径和 CpG 岛甲基化表型（CIMP）途径。本研究招募了 166 名接受结肠镜检查的患者。采集盲肠、横结肠、乙状结肠和直肠的活检样本。在“A型”（ESR1、GATA5、HIC1、HPP1、SFRP1）和“C 型”标志物（MGMT、MLH1、CDKN2A、MINT2、MINT31、IGF2、CACNA1G、NEUROG1、SOCS1、RUNX3）和 LINE-1 上对 DNA 甲基化进行定量。“A型”基因在正常和肿瘤组织中经常发生甲基化，与组织年龄成正比。“C 型”甲基化对肿瘤更为特异。后五个“C 型”标志物组成了 CIMP 面板。计算了平均“A型”和 CIMP 面板甲基化 Z 分数。共有 88 例患者有腺瘤性病变，32 例有近端锯齿状息肉（PSPs），50 例为正常。大多数“A型”基因的甲基化与年龄呈直接相关（ESR1，rho=0.66，P<0.0001），远端甲基化程度更高（ESR1，P<0.0001）。多变量分析显示，“A型”甲基化与结直肠腺瘤呈负相关（比值比=0.23，P<0.001），这是 CIN 型癌症的前体。CIMP 面板甲基化与晚期 PSPs 显著相关（比值比=5.1，P=0.009），这是 CIMP 型癌症的前体。正常黏膜中的 DNA 甲基化随年龄和部位而变化，并与特定途径的病理学相关。未来，结直肠领域可能会提供重要信息，并有可能为临床实践提供信息。
