ABSTRACT

The contribution of DNA-methylation based gene silencing to carcinogenesis is well established. Increasingly, DNA-methylation is examined using genome-wide techniques, with recent public efforts yielding immense data sets of diverse malignancies representing the vast majority of human cancer related disease burden. Whereas mutation events may group preferentially or in high frequency with a given histology, mutations are poor classifiers of tumour type. Here we examine the hypothesis that cancer-specific DNA-methylation reflects the tissue of origin or carcinogenic risk factor, and these methylation abnormalities may be used to faithfully classify tumours according to histology. We present an analysis of 7427 tumours representing 19 human malignancies and 708 normal samples demonstrating that specific tumour changes in methylation can correctly determine site of origin and tumour histology with 86% overall accuracy. Examination of misclassified tumours reveals underlying shared biology as the source of misclassifications, including common cell of origin or risk factors.

摘要

基于 DNA 甲基化的基因沉默对致癌作用的贡献已得到充分证实。越来越多地使用全基因组技术检查 DNA 甲基化，最近的公共努力产生了代表绝大多数人类癌症相关疾病负担的各种恶性肿瘤的大量数据集。尽管突变事件可能优先或以高频率与给定的组织学分组，但突变是肿瘤类型的不良分类器。在这里，我们检验了癌症特异性 DNA 甲基化反映了起源组织或致癌风险因素的假设，并且这些甲基化异常可用于根据组织学对肿瘤进行忠实分类。我们对代表 19 种人类恶性肿瘤的 7427 个肿瘤和 708 个正常样本进行了分析，证明甲基化的特定肿瘤变化可以以 86% 的总体准确度正确确定起源部位和肿瘤组织学。对错误分类肿瘤的检查揭示了潜在的共同生物学作为错误分类的来源，包括共同起源细胞或风险因素。