Marsit Carmen J, Houseman E Andres, Christensen Brock C, Eddy Karen, Bueno Raphael, Sugarbaker David J, Nelson Heather H, Karagas Margaret R, Kelsey Karl T
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Cancer Res. 2006 Nov 1;66(21):10621-9. doi: 10.1158/0008-5472.CAN-06-1687.
The CpG island methylator phenotype (CIMP), thoroughly described in colorectal cancer and to a lesser extent in other solid tumors, is important in understanding epigenetics in carcinogenesis and may be clinically useful for classification of neoplastic disease. Therefore, we investigated whether this putative phenotype exists in exposure-related solid tumors, where somatic gene alterations and enhanced clonal growth are selected for by carcinogens, and examined the ability of methylation profiles to classify malignant disease. We studied promoter hypermethylation of 16 tumor suppressor genes and 3 MINT loci (acknowledged classifiers of CIMP) in 344 bladder cancers, 346 head and neck squamous cell carcinomas (HNSCC), 146 non-small-cell lung cancer (NSCLC), and 71 malignant pleural mesotheliomas (MPM). We employed rigorous statistical methods to examine the distribution of promoter methylation and the usefulness of these profiles for disease classification. In bladder cancer, HNSCC, and NSCLC, there was a significant correlation (P < 0.0001) between methylation of the three MINT loci and methylation index, although the distribution of methylated loci varied significantly across these disease. Although there was a significant (P < 0.001) association between gene methylation profile and disease, rates of misclassification of each disease by their methylation profile ranged from 28% to 32%, depending on the classification scheme used. These data suggest that a form of CIMP exists in these solid tumors, although its etiology remains elusive. Whereas the gene profiles of hypermethylation among examined loci could not unequivocally distinguish disease type, the existence of CIMP and the relative preponderance of hypermethylation in these cancers suggest that methylation analysis may be clinically useful as a targeted screening tool.
CpG岛甲基化表型（CIMP）在结直肠癌中已有详尽描述，在其他实体瘤中也有一定程度的描述，它对于理解致癌过程中的表观遗传学很重要，并且在肿瘤疾病的分类中可能具有临床应用价值。因此，我们研究了这种假定的表型是否存在于暴露相关的实体瘤中，在这些肿瘤中，致癌物会选择体细胞基因改变和增强的克隆生长，并检验了甲基化谱对恶性疾病进行分类的能力。我们研究了344例膀胱癌、346例头颈部鳞状细胞癌（HNSCC）、146例非小细胞肺癌（NSCLC）和71例恶性胸膜间皮瘤（MPM）中16个肿瘤抑制基因和3个MINT位点（公认的CIMP分类指标）的启动子高甲基化情况。我们采用严格的统计方法来检验启动子甲基化的分布以及这些谱对疾病分类的有用性。在膀胱癌、HNSCC和NSCLC中，三个MINT位点的甲基化与甲基化指数之间存在显著相关性（P < 0.0001），尽管甲基化位点的分布在这些疾病之间有显著差异。虽然基因甲基化谱与疾病之间存在显著关联（P < 0.001），但根据所使用的分类方案，每种疾病被其甲基化谱错误分类的比例在28%至32%之间。这些数据表明，这些实体瘤中存在一种形式的CIMP，尽管其病因仍然不明。虽然在所检测位点中高甲基化的基因谱不能明确区分疾病类型，但CIMP的存在以及这些癌症中高甲基化的相对优势表明，甲基化分析作为一种靶向筛查工具可能具有临床应用价值。
