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

ABSTRACT: 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, but systemic analyses of their alterations and biological or clinical implications in human cancer have not been reported. Here we analyzed genomic and molecular alterations in 12 important DNA helicases across 33 cancer types from the TCGA dataset 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. Several drugs are identified to inhibit DNA helicases, with the Auror A kinase inhibitor Danusertib as the strongest candidate. 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 cancer. The close association of DHS with the alt-EJ pathway and cellular proliferation suggests that tumors with higher DHS are sensitive to chemotherapy and radiotherapy; The Auror A kinase inhibitor Danusertib may also inhibit DNA helicases. These findings thus contribute to DNA helicase-based cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217386 | GEO | 2022/11/11

REPOSITORIES: GEO