Hemizygous loss of helicases promotes genomic instability and cancer development
Data files
Dec 19, 2025 version files 30.78 KB
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README.md
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SciAdv_Vossgrone_et_al_2025_2606_2.tar.gz
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Abstract
Cancer mutations perturb key processes, leading to uncontrolled cell proliferation. With the pivotal and specific roles for enzymes at all levels of cellular function and growth, we hypothesized that cancer driver mutations alter specific and recurrent enzymatic functions. Leveraging large pan-cancer genomic data and established driver mutation catalogues, we found a striking frequency of mutations in helicases, enzymes involved in nucleic acid unwinding and processing. We find helicases as the most common cancer driver enzyme family, mutated in two-thirds of all cancers. Based on functional perturbation screens and cancer genomic analyses, we provide evidence that cancers with mutated helicases converge on increased genomic instability and faulty DNA repair. We identify a striking phenotype in cells with loss of the helicase Aquarius (AQR). AQR was an early clonal event exclusively hemizygous lost in cancer genomes, with high levels of genomic instability and mutational signatures indicative of homologous recombination deficiency. Finally, we provide evidence that hemizygous loss is a common tumour suppression mechanism among helicases, present in 35% of all cancers. In summary, using an enzyme-family-driven approach, we uncover helicases as the most frequently mutated enzyme family in cancer, and nominate novel cancer driver candidate genes, including AQR.
This repository contains the code and analysis scripts for the manuscript:
Vossgrone et al. (2025). Hemizygous loss of helicases promotes genomic instability and cancer development. Science Advances.
Repository Structure
- The SciAdv_Vossgrone_et_al_2025_2606_2.tar.gz archive contains:
- pancancer_enzyme_families/
Analysis of enzyme gene families across cancer types. Contains:permutate_gene_list_cancer_type.RPermutation-based gene set enrichment analysis.pancancer_vulcano_plot.RVolcano plot and summary statistics for pan-cancer analysis.sankey_plot.RSankey/alluvial plot for enzyme family relationships.supp/Supplementary scripts and data for this analysis.expression_mutation_lm.RLinear modeling of expression and mutation rates.dNdScv_analysis.R: dN/dS selection analysis pipeline.
- hemizygous_drivers/
Analysis of biallelic and hemizygous driver genes, dependency, and pathway enrichment. Contains:hemizygous_drivers.RMain analysis script for biallelic/hemizygous drivers.
- pancancer_enzyme_families/
Requirements
- R (≥ 4.0 recommended)
- R packages:
dplyr,data.table,ggplot2,tidyr,survcomp,pbapply,effsize,ggalluvial,patchwork,aplot,depmap,ExperimentHub,squash,ggridges,corrplot,ReactomePA,org.Hs.eg.db, and others as called in scripts.
Some scripts require access to large datasets and specific directory structures (see comments in each script for details).
Data Availability
The data used in this repository is not included, but all analyses are based on publicly available datasets from PCAWG and TCGA. Some scripts require access to large or restricted datasets (e.g., TCGA, PCAWG).
Paths to these datasets are specified at the top of each script.
Please update these paths as needed for your environment.
Citation
If you use this code in your research, please cite:
Vossgrone et al. (2025). Hemizygous loss of helicases promotes genomic instability and cancer development. Science Advances.
Contact
For questions or issues, please contact the corresponding authors.
Human subjects data
In this study, we used publicly available data from the TCGA and PCAWG consortia. De-identified IDs provided by these consortia were used throughout the analysis. While we share only the code necessary to reproduce the analysis, access to the data itself must be requested directly from the respective consortia, in accordance with their data access policies.