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.