Methylome analysis in pituitary neuroendocrine tumors. Methylome analysis in pituitary neuroendocrine tumors

Pituitary neuroendocrine tumors (PitNETs), usually benign lesions, can sometimes present with “aggressive” features (rapid growth, local invasiveness, scarce response to conventional treatments). Despite a few genetic alterations have been associated to this clinical behaviour, the role of epigenetic modifications, mainly methylation and miRNAs activity, is now opening new frontiers in this field. We evaluated the methylation profile of 21 PitNETs (11 GH-omas, 10 non-functioning tumors – NFPitNETs) samples from TNS surgery and 5 normal pituitaries, collected at our neurosurgery between 2015 and 2017. DNA was extracted and sequenced, selecting 184,841 target regions. Moreover, methylation profiles were correlated with demographic, radiological, and clinico-pathological features. NFPitNETs showed higher methylation levels vs GH-omas, with 178 differentially methylated regions (DMRs) mainly consisting of non-coding and intronic sequences, and mostly localized in the open sea regions. We also found three hypermethylated genes (C7orf50, GNG7, and BAHCC1), involved in tumorigenesis processes and potentially influencing pituitary tumors pathophysiology. Among clinico-pathological features, only the maximum diameter resulted significantly higher in NFPitNETs. Our data provide further evidence of the complex epigenetic background of pituitary tumors. In line with the current literature, we confirmed a significant prevalence of hypermethylation in NFPitNETs vs GH-omas, whose pathophysiological consequence is yet to be defined.

垂体神经内分泌肿瘤（PitNETs）多为良性病变，但部分可表现出"侵袭性"特征，包括快速生长、局部侵袭以及对常规治疗应答不佳。尽管已有少数遗传变异被证实与该临床表型相关，但表观遗传修饰——主要为甲基化与微小RNA（miRNAs）活性——的作用正为该领域开辟全新研究方向。本研究收集了2015年至2017年间于我院神经外科行经鼻蝶窦（TNS）手术的21例PitNETs样本（11例生长激素瘤[GH-omas]、10例无功能垂体神经内分泌肿瘤[NFPitNETs]）以及5例正常垂体组织样本，对其甲基化谱进行了分析。研究人员提取样本DNA并进行测序，靶向覆盖184841个目标区域。此外，本研究还将甲基化谱与受试者的人口学、影像学以及临床病理特征进行了关联分析。相较于GH-omas，NFPitNETs的甲基化水平更高，共鉴定出178个差异甲基化区域（DMRs），这些区域主要由非编码序列与内含子序列构成，且大多分布于开放海域区域。本研究还发现3个高甲基化基因（C7orf50、GNG7与BAHCC1），这些基因参与肿瘤发生过程，且可能对垂体肿瘤的病理生理机制产生影响。在临床病理特征中，仅无功能垂体神经内分泌肿瘤的最大直径显著更高。本研究数据进一步证实了垂体肿瘤存在复杂的表观遗传调控背景。与现有文献报道一致，本研究证实NFPitNETs相较于GH-omas存在更高的高甲基化发生率，但其病理生理层面的影响仍有待进一步阐明。