结直肠癌中肿瘤抑制基因启动子CpG甲基化及其与临床特征的关系

Promoter CpG methylation of tumor suppressor genes in colorectal cancer and its relationship to clinical features.

作者信息

Lin Shyr-Yi, Yeh Kun-Tu, Chen Willian Tzu-Liang, Chen Hung-Chang, Chen Shou-Tung, Chiou Hung-Yi, Chang Jan-Gowth

机构信息

Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.

出版信息

Oncol Rep. 2004 Feb;11(2):341-8.

PMID:14719065

Abstract

Aberrant promoter methylation of CpG islands of tumor suppressor genes inhibits expression of the genes and may lead to tumorigenesis. We investigated the aberrant methylation profile of potential tumor suppressor genes of p15, p16, SOCS-1, and Wnt signaling pathway in colorectal cancers and correlated the data with clinical findings. Cancerous and nearby non-cancerous tissues of 185 sporadic colorectal cancer samples were studied. Methylation specific PCR was performed to explore the mechanism of inactivation in p15, p16, SOCS-1, E-cadherin, APC, GSK-3beta, and Axin1 genes. Aberrant promoter methylation in p15, p16, SOCS-1, E-cadherin, APC, GSK-3beta, and Axin1 genes were 5.9, 7.0, 3.8, 5.9, 12.4, 2.2, and 0% for cancerous tissues, respectively, whereas the frequencies were 3.8, 0, 0, 7.0, 2.7, 0.5, and 0% for nearby non-cancerous tissues, respectively. The frequency of aberrant promoter methylation of cancerous tissues was significant higher than non-cancerous tissues in p16, SOCS-1, and APC genes (p<0.05) and methylation status of these genes had no clear relationship with clinical parameters. Of the 66 patients who showed at least one aberrant promoter methylation in the tumor-suppressor genes, 5 (7.6%) patients demonstrated multiple methylation phenotype (methylation > or =3) and associated with increased lymph node metastasis (p=0.036). Our findings suggest that inactivation of some tumor suppressor genes through aberrant promoter methylation of CpG islands may play a role in the development of colorectal cancer and methylation inactivation of these genes except p16 and SOCS1 may occur at the precancerous stage. Multiple methylation pathways may be involved in the tumorigenesis of colorectal cancer and associated with aggressiveness of clinical disease.

摘要

肿瘤抑制基因CpG岛的异常启动子甲基化会抑制基因表达，并可能导致肿瘤发生。我们研究了结直肠癌中p15、p16、SOCS-1和Wnt信号通路潜在肿瘤抑制基因的异常甲基化谱，并将数据与临床发现相关联。对185例散发性结直肠癌样本的癌组织及附近非癌组织进行了研究。采用甲基化特异性PCR探讨p15、p16、SOCS-1、E-钙黏蛋白、APC、GSK-3β和Axin1基因的失活机制。癌组织中p15、p16、SOCS-1、E-钙黏蛋白、APC、GSK-3β和Axin1基因的异常启动子甲基化率分别为5.9%、7.0%、3.8%、5.9%、12.4%、2.2%和0%，而附近非癌组织中的频率分别为3.8%、0%、0%、7.0%、2.7%、0.5%和0%。癌组织中p16、SOCS-1和APC基因的异常启动子甲基化频率显著高于非癌组织（p<0.05），且这些基因的甲基化状态与临床参数无明显关系。在66例肿瘤抑制基因中至少有一个异常启动子甲基化的患者中，5例（7.6%）表现出多重甲基化表型（甲基化≥3），且与淋巴结转移增加相关（p=0.036）。我们的研究结果表明，通过CpG岛异常启动子甲基化使一些肿瘤抑制基因失活可能在结直肠癌的发生发展中起作用，除p16和SOCS1外，这些基因的甲基化失活可能发生在癌前阶段。多种甲基化途径可能参与结直肠癌的肿瘤发生，并与临床疾病的侵袭性相关。