Multi-omics analyses reveal biological and clinical insights in recurrent stage I non-small cell lung cancer.

Summary

In 122 stage I NSCLC patients (57 recurrent), integrated genomics/epigenomics/transcriptomics linked solid/micropapillary histology, genomic instability, and APOBEC signatures to recurrence. PRAME was hypomethylated and overexpressed; hypomethylation at a TEAD1 site enabled PRAME transcription, and PRAME inhibition reduced metastasis via EMT gene downregulation. Multi-omics clustering stratified patients into four subgroups with distinct recurrence risks and therapeutic vulnerabilities.

Key Findings

• Solid/micropapillary histology, genomic instability, and APOBEC-related signatures were associated with recurrence.
• PRAME was significantly hypomethylated and overexpressed in recurrent LUAD; TEAD1-site hypomethylation enabled PRAME transcription.
• PRAME inhibition reduced metastasis by downregulating EMT-related genes.
• Single-cell ecosystem changes (AT2 cells with high CNV, exhausted CD8+ T cells, Macro_SPP1) characterized recurrent tumors.
• Multi-omics clustering stratified patients into four subgroups with distinct recurrence risk and therapeutic vulnerabilities.

Clinical Implications

PRAME hypomethylation and expression could serve as biomarkers for recurrence risk and as therapeutic targets; multi-omics stratification may inform adjuvant strategies and surveillance intensity in stage I NSCLC.

Limitations

• Single-cohort design with moderate sample size (n=122) may limit generalizability
• Observational nature precludes causal inference for some associations
• External validation and prospective clinical utility studies are needed

Future Directions

Prospective validation of PRAME-based biomarkers and methylation assays; testing PRAME/TEAD1-axis targeting; integrating multi-omics stratification into adjuvant trial designs for stage I NSCLC.