Esteller Manel, Herman James G
Tumor Biology, The Johns Hopkins Oncology Center, Baltimore, MD 21231, USA.
J Pathol. 2002 Jan;196(1):1-7. doi: 10.1002/path.1024.
Cancer is an epigenetic disease at the same level that it can be considered a genetic disease. In fact, epigenetic changes, particularly DNA methylation, are susceptible to change and are excellent candidates to explain how certain environmental factors may increase the risk of cancer. The delicate organization of methylation and chromatin states that regulates the normal cellular homeostasis of gene expression patterns becomes unrecognizable in the cancer cell. The genome of the transformed cell undergoes simultaneously a global genomic hypomethylation and a dense hypermethylation of the CpG islands associated with gene regulatory regions. These dramatic changes may lead to chromosomal instability, activation of endogenous parasitic sequences, loss of imprinting, illegitimate expression, aneuploidy, and mutations, and may contribute to the transcriptional silencing of tumour suppressor genes. The hypermethylation-associated inactivation affects virtually all of the pathways in the cellular network, such as DNA repair (hMLH1, BRCA1, MGMT, em leader), the cell cycle (p16(INK4a), p14(ARF), p15(INK4b), ...), and apoptosis (DAPK, APAF-1, ...). The aberrant CpG island methylation can also be used as a biomarker of malignant cells and as a predictor of their behaviour, and may constitute a good target for future therapies.
癌症是一种表观遗传疾病，其程度等同于它被视为一种基因疾病。事实上，表观遗传变化，尤其是DNA甲基化，易于改变，并且是解释某些环境因素如何增加癌症风险的绝佳候选因素。在癌细胞中，调节基因表达模式正常细胞稳态的甲基化和染色质状态的精细组织变得无法识别。转化细胞的基因组同时经历全基因组低甲基化以及与基因调控区域相关的CpG岛的密集高甲基化。这些显著变化可能导致染色体不稳定、内源性寄生序列激活、印记丢失、异常表达、非整倍体和突变，并可能导致肿瘤抑制基因的转录沉默。与高甲基化相关的失活几乎影响细胞网络中的所有途径，如DNA修复（hMLH1、BRCA1、MGMT等）、细胞周期（p16(INK4a)、p14(ARF)、p15(INK4b)等）和细胞凋亡（DAPK、APAF-1等）。异常的CpG岛甲基化也可用作恶性细胞的生物标志物及其行为的预测指标，并且可能构成未来治疗的良好靶点。
