DOI: 10.5061/dryad.0rxwdbscs
title: Hemizygous loss of helicases promotes genomic instability and cancer development

description: 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.
description: # 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 biallelic and hemizygous driver
 genes, dependency, and pathway enrichment. Contains: *
 `hemizygous_drivers.R`Main analysis script for biallelic/hemizygous
 drivers. 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.