RepairSig

RepairSig: Inference of DNA Repair Deficiency Mutational Signatures

RepairSig models interactions between DNA damage and DNA repair mechanisms in cancer genomes to identify mutational signatures associated with deficient DNA repair pathways that are obscured by non-additive effects.

Key Features:

• Non-Additivity Modeling: Models interactions between primary mutagenic processes (DNA damage with functional repair) and secondary processes (DNA repair deficiencies) to capture non-additive effects on the mutational landscape.
• Secondary Signature Inference: Assumes known primary process signatures and infers signatures of secondary processes associated with deficient DNA repair pathways.
• Dual-Process Framework: Represents combined contributions of primary and repair-deficient processes for biologically realistic modeling of cancer genome mutagenesis.

Scientific Applications:

• Cancer Genomics: Deconvolves DNA damage and DNA repair contributions to identify mutational signatures linked to deficient DNA repair mechanisms in cancer.
• Targeted Therapy Development: Identifies altered DNA repair pathways to support stratification and therapeutic targeting in oncology.

Methodology:

RepairSig models primary mutagenic signatures together with secondary signatures arising from deficient DNA repair using a non-additive dual-process framework. The approach infers repair deficiency signatures masked by interaction effects and consolidated three previously proposed mismatch repair (MMR) deficiency signatures in breast cancer into a single signature closely matching an experimentally derived profile.