Proteogenomic characterization of skull-base chordoma
Qilin Zhang, Ziyan Xu, Rui Han, Yunzhi Wang, Zhen Ye, Jiajun Zhu, Yixin Cai, Fan Zhang, Jiangyan Zhao, Boyuan Yao, Zhaoyu Qin, Nidan Qiao, Ruofan Huang, Jinwen Feng, Yongfei Wang, Wenting Rui, Fuchu He, Yao Zhao, Chen Ding
Abstract
Skull-base chordoma is a rare, aggressive bone cancer with a high recurrence rate. Despite advances in genomic studies, its molecular characteristics and effective therapies remain unknown. Here, we conduct integrative genomics, transcriptomics, proteomics, and phosphoproteomics analyses of 187 skull-base chordoma tumors. In our study, chromosome instability is identified as a prognostic predictor and potential therapeutic target. Multi-omics data reveals downstream effects of chromosome instability, with RPRD1B as a putative target for radiotherapy-resistant patients. Chromosome 1q gain, associated with chromosome instability and upregulated mitochondrial functions, lead to poorer clinical outcomes. Immune subtyping identify an immune cold subtype linked to chromosome 9p/10q loss and immune evasion. Proteomics-based classification reveals subtypes (P-II and P-III) with high chromosome instability and immune cold features, with P-II tumors showing increased invasiveness. These findings, confirmed in 17 paired samples, provide insights into the biology and treatment of skull-base chordoma. Skull-base chordoma (SBC) is a rare, aggressive bone cancer, but its molecular features remain to be characterised. Here, the authors perform proteogenomic analysis of 187 SBC tumours and identify chromosomal instability as a potential prognostic factor and potential therapeutic targets.