Tumor Genomic and Transcriptomic Analysis Integrated With Liquid Biopsy ctDNA Monitoring: Analytical Validation and...

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Comprehensive genomic profiling (CGP) aids precision oncology by efficiently analyzing tumor DNA.
• Enhancing CGP's clinical utility requires integrating multiple profiling methods.
• A novel strategy combining tumor DNA, mRNA profiling, and liquid biopsy ctDNA monitoring was investigated.

Purpose of the Study:

• To evaluate a novel strategy for comprehensive genomic profiling (CGP).
• To integrate tumor DNA and mRNA profiling with liquid biopsy ctDNA monitoring.
• To enhance the clinical utility of CGP for precision oncology.

Main Methods:

• Simultaneous extraction of DNA and mRNA from 604 archived tumor samples across 12 cancer types.
• Targeted DNA sequencing with high-density probes (HDP) and shallow whole-genome sequencing.
• mRNA transcriptome profiling for fusion variant detection and tissue of origin (TOO) prediction using the OriCUP model.
• Longitudinal ctDNA analysis in 55 metastatic lung cancer patients to predict progression-free survival (PFS).

Main Results:

• HDP DNA sequencing demonstrated higher sensitivity for copy number variations compared to standard panels.
• Combined DNA and mRNA sequencing maximized fusion variant detection in FFPE samples.
• The OriCUP model achieved 87.7% accuracy for primary and 81.4% for metastatic TOO prediction.
• ctDNA profiling identified additional actionable/resistance mutations and correlated with significantly longer PFS in molecular responders.

Conclusions:

• Comprehensive genomic and transcriptomic profiling reveals genetic details beyond DNA-only CGP.
• Integration of ctDNA detection aids in identifying tumor-agnostic mutations and monitoring treatment response.
• This multi-omic approach enhances precision oncology by providing a more complete tumor profile and predictive biomarkers.