# Hemizygous loss of helicases promotes genomic instability and cancer development

## TL;DR

Losing one copy of helicase genes weakens DNA repair, leading to genomic instability and increased cancer risk.

## Contribution

This study identifies helicase gene mutations, particularly hemizygous loss of AQR, as a common and early driver of cancer development.

## Key findings

- Helicases are the most commonly mutated enzyme family in two-thirds of cancers.
- Hemizygous loss of AQR is an early clonal event linked to genomic instability and homologous recombination deficiency.
- Hemizygous loss of helicases is a tumor suppression mechanism present in 35% of cancers.

## Abstract

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 (AQR), 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 AQR, as key potential cancer drivers.

Losing one copy of helicase genes reduces genome protection, leading to DNA damage and higher risk of cancer development.