Gliomas arise through genetic and epigenetic alterations of normal brain cells, although the exact cell of origin for each glioma subtype is unknown. The alteration-induced changes in gene expression and protein function allow uncontrolled cell division, tumor expansion, and infiltration into surrounding normal brain parenchyma. The genetic and epigenetic alterations are tumor subtype and tumor-grade specific. Particular alterations predict tumor aggressiveness, tumor response to therapy, and patient survival. Genetic alterations include deletion, gain, amplification, mutation, and translocation, which result in oncogene activation and tumor suppressor gene inactivation, or in some instances the alterations may simply be a consequence of tumorigenesis. Epigenetic alterations in brain tumors include CpG island hypermethylation associated with tumor suppressor gene silencing, gene-specific hypomethylation associated with aberrant gene activation, and genome-wide hypomethylation potentially leading to loss of imprinting, chromosomal instability, and cellular hyperproliferation. Other epigenetic alterations, such as changes in the position of histone variants and changes in histone modifications are also likely to be important in the molecular pathology of brain tumors. Given that histone deacetylases are targets for drugs that are already in clinical trial, surprisingly little is known about histone acetylation in primary brain tumors. Although a majority of epigenetic alterations are independent of genetic alterations, there is interaction on specific genes, signaling pathways and within chromosomal domains. Next-generation sequencing technology is now the method of choice for genomic and epigenome profiling, allowing more comprehensive understanding of genetic and epigenetic contributions to tumorigenesis in the brain.

中文翻译：

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神经肿瘤学中的分子表观遗传学和遗传学。


神经胶质瘤是通过正常脑细胞的遗传和表观遗传改变而产生的，尽管每种神经胶质瘤亚型的确切起源细胞尚不清楚。基因表达和蛋白质功能的改变引起的变化导致不受控制的细胞分裂、肿瘤扩张和浸润到周围正常脑实质。遗传和表观遗传改变是肿瘤亚型和肿瘤级别特异性的。特定的改变可以预测肿瘤的侵袭性、肿瘤对治疗的反应以及患者的生存率。遗传改变包括缺失、获得、扩增、突变和易位，导致癌基因激活和抑癌基因失活，或者在某些情况下，这些改变可能只是肿瘤发生的结果。脑肿瘤的表观遗传改变包括与抑癌基因沉默相关的 CpG 岛高甲基化、与异常基因激活相关的基因特异性低甲基化，以及可能导致印记丢失、染色体不稳定和细胞过度增殖的全基因组低甲基化。其他表观遗传改变，例如组蛋白变体位置的变化和组蛋白修饰的变化也可能在脑肿瘤的分子病理学中发挥重要作用。鉴于组蛋白脱乙酰酶是已进入临床试验的药物靶标，令人惊讶的是，人们对原发性脑肿瘤中的组蛋白乙酰化知之甚少。尽管大多数表观遗传改变独立于遗传改变，但特定基因、信号传导途径和染色体结构域内存在相互作用。 下一代测序技术现在是基因组和表观基因组分析的首选方法，可以更全面地了解遗传和表观遗传对大脑肿瘤发生的贡献。