OncMTR

OncMTR quantifies missense intolerance across genic subregions to prioritize cancer-driving somatic mutations.

Key Features:

• Missense Tolerance Ratio (OncMTR): Calculates a score for each genic subregion based on the relative frequency of germline versus somatic missense variations, with lower scores indicating higher intolerance.
• Large reference dataset: Leverages the Genome Aggregation Database (gnomAD) comprising 125,748 exomes as a population reference to distinguish germline and somatic variation.
• Predictive capability for hematologic malignancies: Identifies genic subregions depleted of germline variation but enriched for somatic mutations and significantly predicts driver mutations in hematologic malignancies.
• Enrichment analysis: Detects regions with divergent OncMTR scores that are enriched for cancer-relevant protein domains.
• Structural overlay: Maps OncMTR scores onto protein structures to assess the functional importance of specific residues.
• Gene-based collapsing analysis: Validates associations using a rare variant, gene-based collapsing analysis on 394,694 exomes from the UK Biobank.

Scientific Applications:

• Driver mutation prioritization: Prioritizes potential driver missense mutations within genic subregions intolerant to variation.
• Molecular mechanism investigation: Helps map intolerant residues and domains to understand oncogenic mechanisms in cancer genomics research.
• Integration for discovery and validation: Integrates large-scale population exome data with protein-structure information and rare-variant collapsing analyses to support discovery and validation of cancer-associated genes and residues, and to inform basic research and potential clinical translation for diagnosis and treatment strategies.

Methodology:

Computes an OncMTR score per genic subregion as the relative frequency of germline versus somatic missense variations using gnomAD (125,748 exomes), identifies regions depleted of germline and enriched for somatic variants, performs enrichment analysis of protein domains, overlays scores on protein structures, and carries out a rare-variant gene-based collapsing analysis on 394,694 UK Biobank exomes.