The Role of Epigenetic Modification in Tumorigenesis and Progression of Pituitary Adenomas: A Systematic Review of the Literature

Background
Pituitary adenomas (PAs) are commonly occurring neoplasms with diverse endocrine and neurological effects. Although somatic gene mutations are uncommon in sporadic PAs, recent studies lend support to epigenetic modification as a potential cause of tumorigenesis and tumor progression.
Methods
A systematic literature review of the PubMed and Google Scholar databases was conducted to identify abstracts (n=1,082) pertaining to key targets and mechanisms implicated in epigenetic dysregulation of PAs published between 1993-2013. Data regarding histopathological subtype, target genes, mode of epigenetic modification, and clinical correlation were recorded and analyzed.
Results
Of the 47 that studies met inclusion criteria and focused on epigenomic assessment of PAs, only 2 were genome-scale analyses. Current evidence supports epigenetic alteration in at least 24 PA genes, which were categorized into four groups based on function and epigenetic alteration: 1) Sixteen tumor suppressor genes silenced via DNA methylation; 2) Two oncogenes overexpressed via histone acetylation and hypomethylation; 3) Three imprinted genes with selective allelic silencing; and 4) One epigenome writer inducing abnormal genome-scale activity and 5) Two transcription regulators indirectly modifying the genome. Of these, 5 genes (CDKN2A, GADD45y, FGFR2, caspase-8, and PTAG) showed particular susceptibility to epigenetic modification, with abnormal DNA methylation in >50% of PA samples. Several genes displayed correlations between epigenetic modification and clinically relevant parameters, including invasiveness (CDKN2A; DAPK; Rb1), sex (MAGE-A3), tumor size (GNAS1), and histopathological subtype (CDKN2A; MEG3; p27; RASSF1A; Rb1).
Conclusions
Epigenetic modification of selected PA genes may play a key role in tumorigenesis and progression, which may translate into important diagnostic and therapeutic applications.

背景：垂体腺瘤（Pituitary adenomas, PAs）是一类临床常见的肿瘤，可引发多样化的内分泌与神经系统症状。尽管散发性垂体腺瘤中体细胞基因突变较为罕见，但近期研究表明表观遗传修饰可能是其肿瘤发生与进展的潜在诱因。
方法：本研究对PubMed及Google Scholar数据库开展系统性文献回顾，筛选1993年至2013年间发表的、与垂体腺瘤表观遗传失调关键靶点及机制相关的摘要文献，共计1082篇。研究人员记录并分析了与组织病理亚型、靶基因、表观遗传修饰方式及临床相关性相关的数据。
结果：最终有47项符合纳入标准且聚焦垂体腺瘤表观基因组评估的研究被纳入，其中仅2项为全基因组规模分析。现有证据表明，至少24个垂体腺瘤相关基因存在表观遗传改变，依据其功能及表观遗传修饰类型可分为五类：1）16个通过DNA甲基化实现沉默的抑癌基因；2）2个经组蛋白乙酰化及低甲基化实现过表达的癌基因；3）3个存在选择性等位基因沉默的印记基因；4）1个可诱导异常全基因组活性的表观基因组书写因子（epigenome writer）；5）2个可间接修饰基因组的转录调控因子。其中，CDKN2A、GADD45y、FGFR2、caspase-8及PTAG这5个基因对表观遗传修饰尤为易感，在超过50%的垂体腺瘤样本中存在异常DNA甲基化。另有多个基因的表观遗传修饰与临床相关参数存在显著关联，包括肿瘤侵袭性（CDKN2A、DAPK、Rb1）、患者性别（MAGE-A3）、肿瘤体积（GNAS1）及组织病理亚型（CDKN2A、MEG3、p27、RASSF1A、Rb1）。
结论：特定垂体腺瘤基因的表观遗传修饰可能在肿瘤发生与进展中发挥关键作用，这一发现有望转化为重要的临床诊断与治疗应用。