Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Laboratory of System Biology and Computational Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
Epigenetics. 2022 Jan-Feb;17(2):191-201. doi: 10.1080/15592294.2021.1890885. Epub 2021 Mar 5.
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.
DNA 甲基化导致的基因沉默在癌症发生中的作用已得到充分证实。越来越多的研究采用全基因组技术来检测 DNA 甲基化，最近的公共研究努力产生了大量不同恶性肿瘤的数据集，代表了绝大多数与人类癌症相关的疾病负担。虽然突变事件可能优先或高频地与特定的组织学分组，但突变并不能很好地对肿瘤类型进行分类。在这里，我们检验了这样一个假设，即癌症特异性的 DNA 甲基化反映了组织起源或致癌风险因素，这些甲基化异常可以根据组织学准确地对肿瘤进行分类。我们对代表 19 种人类恶性肿瘤和 708 个正常样本的 7427 个肿瘤进行了分析，结果表明，甲基化的特定肿瘤变化可以以 86%的总体准确性正确确定起源部位和肿瘤组织学。对分类错误的肿瘤的检查揭示了潜在的共同生物学作为分类错误的来源，包括共同的起源细胞或风险因素。
