Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0–2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors.

侵袭性垂体神经内分泌瘤 （PitNETs）/腺瘤的特征是尽管进行了手术和所有标准药物治疗和放疗，但仍进行性生长。一部分将转移到大脑和/或远处位置，称为转移性 PitNETs（垂体癌）。由于这些肿瘤的罕见性，对潜在预后标志物的研究受到限制。已经确定了一些复发性体细胞突变，并且尚未在更大的侵袭性和转移性 PitNET 队列中探索表观遗传改变和染色体重排。在这项研究中，我们对来自 64 名侵袭性 （48） 和转移性 （16） 垂体瘤患者的大型国际队列的肿瘤组织标本进行了全基因组甲基化分析，包括拷贝数变异 （CNV） 计算。12 例非浸润性垂体瘤患者 （Knosp 0-2） 在 5 年随访中表现出惰性病程作为对照。在无监督的分层聚类分析中，侵袭性/转移性 PitNETs 与良性垂体瘤分开聚集，并且，当仅分析第一次手术的标本时，确定了三个独立的集群： 侵袭性、转移性和良性 PitNETs。许多影响染色体臂和整个染色体的 CNV 事件在侵袭性和转移性中很常见，而良性肿瘤的染色体拷贝数正常，只有很少的改变。全基因组甲基化分析揭示了不同的 CNV 谱，并且侵袭性/转移性和良性垂体瘤之间有明显的区别，可能为识别这些在首次手术时预后较差的肿瘤提供生物标志物。 这些数据可以改进随访程序，并有助于在患有侵袭性或转移性垂体瘤或有发展风险的垂体瘤患者中及时引入辅助治疗。