Toyooka S, Toyooka K O, Maruyama R, Virmani A K, Girard L, Miyajima K, Harada K, Ariyoshi Y, Takahashi T, Sugio K, Brambilla E, Gilcrease M, Minna J D, Gazdar A F
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-8563, USA.
Mol Cancer Ther. 2001 Nov;1(1):61-7.
Aberrant methylation of CpG islands in promoter regions of tumor cells is one of the major mechanisms for silencing of tumor suppressor genes. We determined the frequency of aberrant promoter methylation of the p16, adenomatous polyposis coli (APC), H-cadherin (CDH13), glutathione S-transferase P1 (GSTP1), O6-methylguanine-DNA-methyltransferase (MGMT), retinoic acid receptor beta-2 (RAR beta), E-cadherin (CDH1), and RAS association domain family 1A (RASSF1A) genes in 198 tumors consisting of small cell lung cancers [SCLCs (n = 43)], non-small cell lung cancers [NSCLCs (n = 115)], and bronchial carcinoids (n = 40). The profile of methylated genes in the two neuroendocrine tumors (SCLC and carcinoids) were very different from that of NSCLC. However, whereas the overall pattern of aberrant methylation of carcinoids was similar to that of SCLC, carcinoids had lower frequencies of methylation for some of the genes tested. There were also significant differences in the methylation profiles between the two major types of NSCLC, adenocarcinoma and squamous cell carcinoma. We performed cluster analysis and found that SCLCs clustered with other SCLCs and carcinoids but not with NSCLCs, whereas the NSCLCs tended to cluster together. Within NSCLCs, adenocarcinomas and squamous cell carcinomas clustered with their respective histological types. Finally, we compared the methylation profiles of SCLC and NSCLC tumors and their respective cell lines (n = 44). In general, methylation frequencies were higher in tumor cell lines, but these differences were seldom significant. Thus, tumor cell lines appear to be suitable models to study aberrant DNA methylation. We conclude that SCLC, carcinoids, squamous cell carcinomas, and adenocarcinomas of the lung have unique profiles of aberrant methylation. Our findings should help us understand differences in the pathogenetic mechanisms of lung cancers.
肿瘤细胞启动子区域CpG岛的异常甲基化是肿瘤抑制基因沉默的主要机制之一。我们测定了198例肿瘤中p16、腺瘤性息肉病基因（APC）、H-钙黏蛋白（CDH13）、谷胱甘肽S-转移酶P1（GSTP1）、O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）、维甲酸受体β-2（RARβ）、E-钙黏蛋白（CDH1）和RAS关联结构域家族1A（RASSF1A）基因启动子异常甲基化的频率，这些肿瘤包括小细胞肺癌[SCLC（n = 43）]、非小细胞肺癌[NSCLC（n = 115）]和支气管类癌（n = 40）。两种神经内分泌肿瘤（SCLC和类癌）的甲基化基因谱与NSCLC的非常不同。然而，虽然类癌的异常甲基化总体模式与SCLC相似，但类癌中某些检测基因的甲基化频率较低。两种主要类型的NSCLC，即腺癌和鳞状细胞癌之间的甲基化谱也存在显著差异。我们进行了聚类分析，发现SCLC与其他SCLC和类癌聚类在一起，而不与NSCLC聚类，而NSCLC倾向于聚类在一起。在NSCLC中，腺癌和鳞状细胞癌与其各自的组织学类型聚类在一起。最后，我们比较了SCLC和NSCLC肿瘤及其各自细胞系（n = 44）的甲基化谱。一般来说，肿瘤细胞系中的甲基化频率较高，但这些差异很少有统计学意义。因此，肿瘤细胞系似乎是研究异常DNA甲基化的合适模型。我们得出结论，肺的SCLC、类癌、鳞状细胞癌和腺癌具有独特的异常甲基化谱。我们的发现应有助于我们理解肺癌发病机制的差异。
