Hemizygous loss of helicases promotes genomic instability and cancer development

Sep 22, 2026

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Cancer driver mutations disrupt essential cellular processes, enabling uncontrolled proliferation. By integrating large pan-cancer genomic datasets with curated mutation catalogs, the study identifies frequent mutations in helicases, nucleic-acid unwinding and processing enzymes, as the most commonly mutated driver enzyme family, altered in two-thirds of cancers. Functional screens and genomic analyses link helicase dysfunctions to genomic instability and impaired DNA repair, including recurrent Aquarius helicase (AQR) hemizygous deletions associated with high instability and homologous recombination deficiency signatures. Hemizygous loss emerges as a broader tumor-suppressive mechanism in helicases across 35% of cancers, highlighting potential therapeutic avenues.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Driver mutations and challenges in identifying cancer drivers

Enzyme activity as an orthogonal approach

Results

Pan-cancer mutation enrichment analysis reveals helicases as a recurrently mutated enzyme family

CANCER Hemizygous loss of helicases promotes genomic instability and cancer development Karolin Voßgröne1†, Francesco Favero1,2†, Krushanka Kashyap1, Francisco G. Rodríguez-González1,2, André V. Olsen1,2, Xin Li1, Balca R. Mardin3‡, Joachim Weischenfeldt1,2,4*, Claus S. Sørensen1* 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 ofall 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. copyright © 2026 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution license 4.0 (cc BY) . INTRODUCTION Cancer is fueled by driver mutations in genes that promote and orchestrate cancer development and progression. The mutated oncogenes and tumor suppressor genes (TSGs) have classically been identified on the basis of the recurrence of aberrations affecting the genes, with gain-of-function (GoF) mutations of oncogenes and loss-of-function (LoF) mutations ofTSGs. Cancer drivers have been challenging to identify due to their context dependence, both in terms oftissue type, cell of origin, and dependence on dysregulated pathways and other cancer genes. Statistical concepts and approaches have been developed to identify recurrently mutated genes within and among different cancer types ( 1, 2) and enrichment of mutations in specific pathways (3, 4) . Despite advances, genetic alterations contributing to tumor development and progression are not well characterized for a substantial number of cancers. Current approaches seek to identify genes or loci that are more frequently mutated than expected by chance but do generally not consider a priori the function or activity of the affected genes. An orthogonal approach is to harness information on the molecular function and activity of the mutated protein. A key function is enzymatic activity, such as phosphorylation and dephosphorylation of proteins by kinases and phosphatases, respectively. Enzymatic activities catalyze thousands of biochemical reactions in the cell (5). Specifically, biochemical classification of enzymes is based on common biochemical activity rather than sequence similarity. Accordingly, sequences within an enzyme class are often highly divergent; thus, the term families is used for sequence-related enzyme groups within a class (6) . A number of enzyme families are associated with many 1Biotech Research and innovation centre, University of copenhagen, Ole Maaløes Vej 5, copenhagen 2200 n, denmark. 2Finsen laboratory, copenhagen University hospital– Rigshospitalet, copenhagen, denmark.3BioMedX institute (Gmbh), heidelberg, Germany. 4charité–Universitätsmedizin Berlin, Berlin, Germany. *[corresponding author. email: claus.storgaard@bric.ku.dk](corresponding author. email: claus.storgaard@bric.ku.dk) (c.S.S.); joachim.weischenfeldt@ [bric.ku.dk](bric.ku.dk) (J.W.) †these authors contribute

FAQs

How does the study identify cancer drivers at the level of enzyme families?

It combines pan-cancer genomic mutation data with curated mutation catalogs, then aggregates signals by enzyme-wide molecular activity categories and mutational frequencies to find recurrent driver functions.

What role do helicases play according to the results?

Helicases are the most frequently mutated cancer driver enzyme family. Helicas dysfunction contributes to genomic instability and faulty DNA repair.

What is Aquarius helicase (AQR), and why is it important?

AQR shows a marked phenotype with recurrent hemizygous deletions as an early clonal event. These deletions associate with high genomic instability and homologous recombination deficiency signatures.

Sep 22, 2026

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