FIREFLY

Overview

FIREFLY is a computational method for identifying non-coding regulatory dysregulation at the gene-set level. It integrates protein-binding microarray (PBM) data for transcription factors (TFs) with somatic promoter-mutation calls from whole-genome sequencing to identify gene sets enriched for promoter mutations that alter TF binding and produce concordant transcriptional dysregulation. FIREFLY scores are computed at the gene-set level rather than per-mutation, making it sensitive to the diffuse signal of individually rare non-coding mutations.

Used by

• Applied to 70 CCA WGS samples and 6,639 mutated promoters in the ICGC cholangiocarcinoma study; integrating protein-binding microarray data for 486 TFs identified four gene sets enriched for promoter mutations that alter TF binding and produce concordant transcriptional dysregulation. Two of the four sets are PRC2/H3K27me3 targets preferentially mutated in Cluster 1 (CpG-island hypermethylation subtype) PMID:28667006

Notes

• Developed in the context of the ICGC cholangiocarcinoma study; does not predict directionality of expression change for individual mutations since TFs can be activators or repressors.
• Gene-set-level effects are inferred without per-mutation directionality.
• Whether the approach recovers analogous signals in other cancer types remains an open empirical question.

Sources

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