顽固性颅咽管瘤(ACP)是儿童中最常见的垂体区肿瘤。目前尚无有效药物可用，病人间异质性显著。本研究旨在基于多组学特征、影像学和组织学特点，识别ACP的分子亚型，以预测对抗炎治疗和免疫疗法的反应。我们分析了包括119例ACP和23例乳头状颅咽管瘤在内的142例中国病例。进行了全外显子测序(包括复发病例151个)，RNA测序(83个肿瘤)和DNA甲基组测序(95个肿瘤)。我们运用共识聚类和非负矩阵分解进行亚组划分，使用Cox回归进行预后评估。我们识别出三个不同的分子亚型：WNT、ImA和ImB。WNT亚型显示较高的Wnt/β-连环蛋白信号通路活性，有较多上皮细胞和更为固实型肿瘤。ImA和ImB亚型激活了炎症和干扰素反应通路，有增强的免疫细胞浸润和更多囊性肿瘤。只有ImA样本中激活了丝裂原激活蛋白激酶(MEK/MAPK)信号通路，而IL-6和上皮间质转变标志物在ImB组中高表达，该组以儿童为主。ImA亚型中的星形胶质细胞增生程度明显升高，肿瘤浸润前缘有严重的指状突出。分子亚型划分是一项独立的预后因素，WNT组的事件无进展生存期比ImB组长(Cox，P = 0.04)。ImA/ImB病例对免疫检查点阻断治疗(immune checkpoint blockade therapy, ICB)的反应更为可能(P <0.01)。在亚型标记物的初步筛选中，WNT的CD38明显下调，与ImA和ImB(P = 0.01)相比。ACP包括三个分子亚型，具有不同的影像学和组织学特征。WNT亚型的预后较好，而ImB组更有可能从ICB治疗中获益。Copyright © 2023中国医学会，由Wolters Kluwer, Inc. 根据CC-BY-NC-ND许可证进行制作。

Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies.Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (83 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively.Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/β-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox, P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group (P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB (P = 0.01).ACP comprises three molecular subtypes with distinct imaging and histological features. The prognosis of the WNT type is better than that of the ImB group, which is more likely to benefit from the ICB treatment.Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.