Hemizygous loss of helicases promotes genomic instability and cancer development

Cancer mutations perturb key processes, driving uncontrolled cell proliferation. With critical roles of enzymes in cell function and growth, we hypothesized that cancer driver mutations alter specific and recurrent enzymatic functions. Leveraging large pan-cancer genomic datasets and curated mutation catalogs, we identified frequent mutations in helicases, enzymes involved in nucleic acid unwinding and processing. Helicases emerged as the most commonly mutated cancer driver enzyme family, altered in two-thirds of all cancers. Functional screens and genomic analyses revealed that helicase dysfunctions contribute to genomic instability and faulty DNA repair. We observed a marked phenotype of Aquarius helicase (<i>AQR</i>), which was recurrently hemizygously deleted as an early clonal event in cancer genomes. These deletions were associated with high genomic instability and homologous recombination deficiency signatures. Furthermore, we found hemizygous loss to be a common tumor suppression mechanism among helicases, present in 35% of all cancers. Overall, our enzyme-family approach highlights helicases, including <i>AQR</i>, as key potential cancer drivers.