FIREVAT

FIREVAT refines somatic variant calls in human cancer genomes by leveraging Pan-cancer Analysis of Whole Genomes (PCAWG)-derived mutational signatures to distinguish sequencing artifacts from true somatic mutations.

Key Features:

• R package implementation: Implemented as an R package for computational variant refinement.
• PCAWG mutational signatures: Leverages mutational signatures identified by the Pan-cancer Analysis of Whole Genomes (PCAWG) study to evaluate and refine somatic mutations.
• Input format: Accepts Variant Call Format (VCF) files as input.
• Report generation: Produces a comprehensive report detailing the variant refinement process and outcomes.
• Improved accuracy: Removes artifactual point mutations to improve precision and specificity in identifying true somatic mutations.
• Orthogonal validation: Validated using orthogonal sequencing datasets comprising 384 tumor samples against ground truth benchmarks.
• Comparative performance: Demonstrated superior performance relative to existing filtering approaches.
• TCGA validation: Validated on 308 The Cancer Genome Atlas (TCGA) samples, identifying more biologically and clinically relevant mutational signatures and enriching sequence contexts associated with experimental errors.

Scientific Applications:

• Variant refinement for precision oncology: Refining somatic variant calls in cancer genome studies to support precision oncology analyses.
• Artifact discrimination: Distinguishing sequencing-induced artifactual point mutations from true somatic variants in tumor sequencing data.
• Mutational signature analysis: Detecting and enriching PCAWG-derived mutational signatures relevant to cancer biology and clinical interpretation.
• Quality control and validation: Providing orthogonal validation of variant calls using independent sequencing datasets.
• Data improvement for downstream analyses: Improving variant data quality for prognostic and therapeutic decision-making.

Methodology:

FIREVAT uses PCAWG-derived mutational signatures to evaluate and refine somatic variants from a Variant Call Format (VCF) file and outputs a comprehensive report; performance was validated on orthogonal sequencing datasets (384 tumor samples) and 308 TCGA samples.