Esteller Manel
Cancer Epigenetics Laboratory, Molecular Pathology Program, Centro Nacional de Investigaciones Oncologicas, 28029 Madrid, Spain.
Oncogene. 2002 Aug 12;21(35):5427-40. doi: 10.1038/sj.onc.1205600.
We have come a long way since the first reports of the existence of aberrant DNA methylation in human cancer. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation. CpG island hypermethylation has been described in almost every tumor type. Many cellular pathways are inactivated by this type of epigenetic lesion: DNA repair (hMLH1, MGMT), cell cycle (p16(INK4a), p15(INK4b), p14(ARF)), apoptosis (DAPK), cell adherence (CDH1, CDH13), detoxification (GSTP1), etc em leader However, we still know little of the mechanisms of aberrant methylation and why certain genes are selected over others. Hypermethylation is not an isolated layer of epigenetic control, but is linked to the other pieces of the puzzle such as methyl-binding proteins, DNA methyltransferases and histone deacetylase, but our understanding of the degree of specificity of these epigenetic layers in the silencing of specific tumor suppressor genes remains incomplete. The explosion of user-friendly technologies has given rise to a rapidly increasing list of hypermethylated genes. Careful functional and genetic studies are necessary to determine which hypermethylation events are truly relevant for human tumorigenesis. The development of CpG island hypermethylation profiles for every form of human tumors has yielded valuable pilot clinical data in monitoring and treating cancer patients based in our knowledge of DNA methylation. Basic and translational will both be needed in the near future to fully understand the mechanisms, roles and uses of CpG island hypermethylation in human cancer. The expectations are high.
自从首次报道人类癌症中存在异常DNA甲基化以来，我们已经取得了长足的进展。位于肿瘤抑制基因启动子区域的CpG岛高甲基化现已被确认为基因失活的重要机制。几乎在每种肿瘤类型中都有CpG岛高甲基化的描述。许多细胞通路因这种表观遗传损伤而失活：DNA修复（hMLH1、MGMT）、细胞周期（p16(INK4a)、p15(INK4b)、p14(ARF)）、细胞凋亡（DAPK）、细胞黏附（CDH1、CDH13）、解毒（GSTP1）等。然而，我们对异常甲基化的机制以及为何某些基因被选中而其他基因未被选中仍然知之甚少。高甲基化并非表观遗传控制的孤立层面，而是与甲基结合蛋白、DNA甲基转移酶和组蛋白脱乙酰酶等拼图的其他部分相关联，但我们对这些表观遗传层面在特定肿瘤抑制基因沉默中的特异性程度的理解仍不完整。用户友好型技术的激增导致高甲基化基因的清单迅速增加。进行仔细的功能和遗传学研究以确定哪些高甲基化事件与人类肿瘤发生真正相关是必要的。针对每种人类肿瘤形式开发CpG岛高甲基化图谱，基于我们对DNA甲基化的了解，已在癌症患者的监测和治疗中产生了有价值的初步临床数据。在不久的将来，基础研究和转化研究都将是充分理解CpG岛高甲基化在人类癌症中的机制、作用和用途所必需的。人们对此期望很高。
