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 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.