神经内分泌肿瘤（NEN）包括由各种器官中的神经内分泌细胞产生的肿瘤，包括胃肠道、胰腺、肾上腺和副神经节。尽管取得了进展，但仅根据病理数据准确预测胃肠胰 (GEP) NEN 的侵袭性仍然具有挑战性，从而限制了最佳临床管理。我们之前的研究揭示了原钙粘蛋白 PCDHGC3 基因的高甲基化与源自副神经节和肾上腺髓质的神经内分泌肿瘤之间的重要联系。这种表观遗传改变与转移潜力增加和琥珀酸脱氢酶复合物（SDH）功能障碍有关。当前的研究扩展了这一发现，在包含 34 例病例的队列中探索了 GEP-NEN 背景下的 PCDHGC3 基因甲基化。我们发现 29% 的 GEP-NEN 中 PCDHGC3 启动子高甲基化，与胰腺（泛）NEC 以及胃肠道和泛起源的神经内分泌肿瘤（NET）相比，胃肠道（GI）神经内分泌癌（NEC）的患病率显着更高。重要的是，这些发现在最大的多中心 GEP-NEN 队列之一中得到了验证。机制分析表明，PCDHGC3 高甲基化与 SDH 突变或蛋白质丢失无关，表明不依赖于 SDH 的表观遗传机制。临床上，PCDHGC3 高甲基化成为一个重要的预后因素，与两个患者队列的总体生存率降低相关。值得注意的是，虽然 PCDHGC3 高甲基化与 NEC 的标志 TP53 体细胞突变表现出很强的相关性，但其预测价值超过了 TP53 突变，区分 GI 的曲线下面积 (AUC) 为 0.95 (95% CI 0.83-1.0) -来自 GI-NET 的 NEC，强调其卓越的预测性能。总之，我们的研究结果将 PCDHGC3 甲基化状态定位为有效对 GI-NEN 患者进行分层的有前途的分子生物标志物。这一发现有可能通过实现更精确的风险评估和量身定制的治疗策略来推进患者护理。 © 2024 作者。约翰·威利出版的《病理学杂志》

Neuroendocrine neoplasms (NENs) encompass tumors arising from neuroendocrine cells in various organs, including the gastrointestinal tract, pancreas, adrenal gland, and paraganglia. Despite advancements, accurately predicting the aggressiveness of gastroenteropancreatic (GEP) NENs based solely on pathological data remains challenging, thereby limiting optimal clinical management. Our previous research unveiled a crucial link between hypermethylation of the protocadherin PCDHGC3 gene and neuroendocrine tumors originating from the paraganglia and adrenal medulla. This epigenetic alteration was associated with increased metastatic potential and succinate dehydrogenase complex (SDH) dysfunction. Expanding upon this discovery, the current study explored PCDHGC3 gene methylation within the context of GEP-NENs in a cohort comprising 34 cases. We uncovered promoter hypermethylation of PCDHGC3 in 29% of GEP-NENs, with a significantly higher prevalence in gastrointestinal (GI) neuroendocrine carcinomas (NECs) compared with both pancreatic (Pan) NECs and neuroendocrine tumors (NETs) of GI and Pan origin. Importantly, these findings were validated in one of the largest multi-center GEP-NEN cohorts. Mechanistic analysis revealed that PCDHGC3 hypermethylation was not associated with SDH mutations or protein loss, indicating an SDH-independent epigenetic mechanism. Clinically, PCDHGC3 hypermethylation emerged as a significant prognostic factor, correlating with reduced overall survival rates in both patient cohorts. Significantly, whereas PCDHGC3 hypermethylation exhibited a strong correlation with TP53 somatic mutations, a hallmark of NEC, its predictive value surpassed that of TP53 mutations, with an area under the curve (AUC) of 0.95 (95% CI 0.83-1.0) for discriminating GI-NECs from GI-NETs, highlighting its superior predictive performance. In conclusion, our findings position PCDHGC3 methylation status as a promising molecular biomarker for effectively stratifying patients with GI-NENs. This discovery has the potential to advance patient care by enabling more precise risk assessments and tailored treatment strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.