Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance

• Published in: Chinese medical journal 2024-04, Vol.137 (7), p.859-870
• Main Authors: Wang, Xianlong, Zhao, Chuan, Lin, Jincheng, Liu, Hongxing, Zeng, Qiuhong, Chen, Huadong, Wang, Ye, Xu, Dapeng, Chen, Wen, Xu, Moping, Zhang, En, Lin, Da, Lin, Zhixiong
• Format: Article
• Language: English
• Subjects: Algorithms; Anti-inflammatory agents; Bone cancer; Brain research; Cancer therapies; Consortia; Cystic fibrosis; DNA methylation; Ethics; Genes; Genetic testing; Genomes; Genomics; Histology; Immunotherapy; Kinases; Medical imaging; Medical prognosis; Mutation; Patients; Pediatrics; Proteomics; Tumors
• ISSN: 0366-6999; 2542-5641
• DOI: 10.1097/CM9.0000000000002774

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 (84 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