University of California, San Francisco, CA, USA.
Adv Exp Med Biol. 2013;754:313-38. doi: 10.1007/978-1-4419-9967-2_15.
Accurate detection of epimutations in tumor cells is crucial for -understanding the molecular pathogenesis of cancer. Alterations in DNA methylation in cancer are functionally important and clinically relevant, but even this well-studied area is continually re-evaluated in light of unanticipated results, such as the strong association between aberrant DNA methylation in adult tumors and polycomb group profiles in embryonic stem cells, cancer-associated genetic mutations in epigenetic regulators such as DNMT3A and TET family genes, and the discovery of altered 5-hydroxymethylcytosine, a product of TET proteins acting on 5-methylcytosine, in human tumors with TET mutations. The abundance and distribution of covalent histone modifications in primary cancer tissues relative to normal cells is an important but largely uncharted area, although there is good evidence for a mechanistic role of cancer-specific alterations in histone modifications in tumor etiology, drug response, and tumor progression. Meanwhile, the discovery of new epigenetic marks continues, and there are many useful methods for epigenome analysis applicable to primary tumor samples, in addition to cancer cell lines. For DNA methylation and hydroxymethylation, next-generation sequencing allows increasingly inexpensive and quantitative whole-genome profiling. Similarly, the refinement and maturation of chromatin immunoprecipitation with next-generation sequencing (ChIP-seq) has made possible genome-wide mapping of histone modifications, open chromatin, and transcription factor binding sites. Computational tools have been developed apace with these epigenome methods to better enable accurate interpretation of the profiling data.
准确检测肿瘤细胞中的表观突变对于理解癌症的分子发病机制至关重要。癌症中 DNA 甲基化的改变在功能上很重要，临床上也很相关，但即使是这个研究得很好的领域，也在不断地根据意想不到的结果进行重新评估，例如成年肿瘤中异常的 DNA 甲基化与胚胎干细胞中多梳组蛋白的强烈关联、表观遗传调节剂（如 DNMT3A 和 TET 家族基因）中的癌症相关遗传突变，以及在 TET 突变的人类肿瘤中发现的改变的 5-羟甲基胞嘧啶（TET 蛋白作用于 5-甲基胞嘧啶的产物）。相对于正常细胞，原发性癌症组织中组蛋白共价修饰的丰度和分布是一个重要但在很大程度上尚未被探索的领域，尽管有充分的证据表明癌症特异性组蛋白修饰改变在肿瘤病因学、药物反应和肿瘤进展中具有机制作用。与此同时，新的表观遗传标记不断被发现，除了癌细胞系之外，还有许多适用于原发性肿瘤样本的表观基因组分析有用方法。对于 DNA 甲基化和羟甲基化，下一代测序允许进行越来越便宜和定量的全基因组分析。同样，与下一代测序的染色质免疫沉淀（ChIP-seq）的改进和成熟使得能够对组蛋白修饰、开放染色质和转录因子结合位点进行全基因组作图。随着这些表观基因组方法的发展，计算工具也在迅速发展，以便更好地准确解释分析数据。
