FunVar Functional Impact Events (FIEs) in cancer

FunVar-TRACERx

"Gene duplication is associated with gene diversification and potential neofunctionalisation in lung cancer evolution" (Ashford et al 2025 )¹

Repository includes FunVar-FIE scoring algorithm, FIE-gene/FIE-FunFam diversity scoring, Cancer Effect Size (CES) calculations, benchmarking, and associated datasets.

In addition, FunVar-FIE scoring relies on previously published methods:

• MutClust - Calculation of significant cancer mutation clusters on protein structures by permutation testing

• MutFam - Mutationally enriched CATH Functional Families (used as a component of FIE-scores)

Benchmarking and resources are described in /benchmark/README.md.

Note: some large files (>50Mb) are zipped in the data directory and require extracting prior to running CES.

Paths and descriptions

path		Description
./script		Collated scripts including summary calculations and statistics
	/fie_scoring	Run FunVar-FIE scoring on a pre-processed mutation dataset
	/fie_scoring/packages	Classes for mutations, FIEs and FunVar scoring
	/fie_scoring/resources	aaindex package
	/fie_scoring/working	FIE score outputs
	/diversity_analysis	Hill-Shannon diversity calculations & plots
	/ces	Cancer Effect Size calculations with cancereffectsizeR for FIEs grouped by FunFam and alignment residue number
	/benchmark	Binary classification benchmarking (see: /benchmark/README.md)
./data		General datasets for figures, calculations, and FIE scoring
	/cath	CATH v4.2 FunFams and UniProt mapping
	/benchmark/minimal	Datasets for benchmarking and comparison with other structure-based driver prediction algorithms
./plot		Plots for FunVar scores by CGC gene category, long-tail of FIEs per gene, and CES outputs

Running FunVar-FIE scoring

# Create a virtual environment and install libraries
# cd <git-cloned-dir>
python -m venv .venv
source .venv/bin/activate
pip install --upgrade pip
pip install -r requirements.txt

# Run FIE-scoring with dataset of mutations annotated 
# with clusters and functional sites 
python script/fie_scoring/nfe_main.py
# Output written to script/fie_scoring/working/

This work is licensed under a Creative Commons Attribution 4.0 International License.

AAindex data is provided by Kawashima et al ². aaindex.py licensed under a BSD-2-Clause license. Further info: https://pymolwiki.org/AAindex

Footnotes

1. Ashford P, Frankell AM, Piszka Z, Pang CSM, Abbasian M, Bakir MA, Jamal-Hanjani M, McGranahan N, Swanton C, Orengo CA. Gene duplication is associated with gene diversification and potential neofunctionalization in lung cancer evolution. Genome Res. 2026 Mar 2;36(3):561-577. doi: 10.1101/gr.278663.123. PMID: 41714147; PMCID: PMC12951968. https://doi.org/10.1101/gr.278663.123 ↩

2. Kawashima, S. and Kanehisa, M.; AAindex: amino acid index database. Nucleic Acids Res. 28, 374 (2000). [PMID:10592278] https://www.genome.jp/aaindex/aaindex_help.html ↩