Hemizygous loss of helicases promotes genomic instability and cancer development

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 indi..., 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., , # Hemizygous loss of helicases promotes genomic instability and cancer development

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.R`Permutation-based gene set enrichment analysis.
* `pancancer_vulcano_plot.R`Volcano plot and summary statistics for pan-cancer analysis.
* `sankey_plot.R`Sankey/alluvial plot for enzyme family relationships.
* `supp/`Supplementary scripts and data for this analysis.
* `expression_mutation_lm.R`Linear modeling of expression and mutation rates.
* `dNdScv_analysis.R`: dN/dS selection analysis pipeline.
* **hemizygous_drivers/**
Analysis of b...