Proteogenomic characterization of skull-base chordoma

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Skull-base chordoma is a rare, aggressive bone cancer with a high recurrence rate.
• Its molecular underpinnings and effective therapies remain largely unknown despite genomic research.
• Understanding these factors is crucial for improving patient outcomes.

Purpose of the Study:

• To investigate the molecular characteristics of skull-base chordoma using multi-omics approaches.
• To identify prognostic predictors and potential therapeutic targets.
• To elucidate the biological mechanisms driving tumor progression and treatment resistance.

Main Methods:

• Integrative analysis of genomics, transcriptomics, proteomics, and phosphoproteomics data from 187 skull-base chordoma tumors.
• Correlation of molecular alterations with clinical outcomes and immune profiles.
• Validation in 17 paired tumor samples.

Main Results:

• Chromosome instability identified as a significant prognostic predictor and potential therapeutic target.
• RPRD1B implicated as a target for radiotherapy-resistant patients.
• Chromosome 1q gain linked to increased chromosome instability, mitochondrial function, and poorer outcomes.
• An immune-cold subtype associated with chromosome 9p/10q loss and immune evasion discovered.
• Proteomics revealed subtypes (P-II, P-III) with high chromosome instability and immune cold features, P-II exhibiting increased invasiveness.

Conclusions:

• Chromosome instability is a central driver in skull-base chordoma biology and clinical behavior.
• Targeting chromosome instability, RPRD1B, and immune evasion pathways may offer new therapeutic strategies.
• Multi-omics profiling provides critical insights into skull-base chordoma heterogeneity and treatment resistance.