Widespread genomic/molecular alterations of DNA helicases and their clinical/therapeutic implications across human cancer

DNA helicases are essential to genomic stability by regulating DNA metabolisms and their loss-of-function mutations lead to genomic instability and predisposition to cancer. Paradoxically, overexpression of DNA helicases is observed in several cancers. Here we analyzed genomic and molecular alterations in 12 important DNA helicases in TCGA pan-cancers to provide an overview of their aberrations. Significant expression heterogeneity of 12 DNA helicases was observed. We calculated DNA helicase score (DHS) based on their expression, and categorized tumors into high, low and intermediate subtypes. High DHS subtypes were robustly associated with stemness, proliferation, hyperactivated oncogenic signaling, longer telomeres, total mutation burden, copy number alterations (CNAs) and shorter survival. Importantly, tumors with high DHSs exhibited stronger expression of alternative end-join (alt-EJ) factors, indicative of sensitivity to chemo- and radio-therapies. High DHSs were also associated with homologous recombination deficiency (HRD), BRCA1/2 mutations and sensitivity to PARP inhibitors. Moreover, several drugs are identified to inhibit DNA helicases, with the Auror A kinase inhibitor Danusertib as the strongest candidate that was confirmed experimentally. The aberrant expression of DNA helicases was associated with CNAs, DNA methylation and m6A regulators. Our findings thus reveal widespread dysregulation of DNA helicases and their broad connection with featured oncogenic aberrations across human cancers. The close association of DHS with the alt-EJ pathway and HRD, and identification of Danusertib as a putative DNA helicase inhibitor have translational significance. Taken together, these findings will contribute to DNA helicase-based cancer therapy.

Automated summary

DNA helicases play a crucial role in maintaining genomic stability, and mutations in these genes can lead to genomic instability and cancer susceptibility. Interestingly, overexpression of DNA helicases is observed in certain cancers. In this study, genomic and molecular alterations in 12 important DNA helicases were analyzed across various types of cancers. The study revealed significant expression heterogeneity among these helicases, and tumors were classified into subtypes based on their DNA helicase score. The high DNA helicase score subtypes were associated with stemness, proliferation, oncogenic signaling, longer telomeres, more mutations, copy number alterations, and shorter survival. Furthermore, high DNA helicase scores were linked to sensitivity to chemo- and radio-therapies, as well as defects in DNA repair pathways like homologous recombination deficiency. Importantly, a potential DNA helicase inhibitor, Danusertib, was identified in this study. These findings highlight the dysregulation of DNA helicases in cancer and their potential as therapeutic targets.