Abstract A018: Lung cancer associated DNA Damageome reveals a genome destabilizing role of Aquaporin 3

Abstract

Abstract Lung cancer is a multifactorial disease caused by both environmental exposures and genetic factors. Genome and transcriptome-wide association studies (GWAS and TWAS) successfully identified many genetic variants and candidate causal genes associated with lung cancer. However, the lack of functional studies of these genes remains a major bottleneck to clinical translation. Recently, we discovered that large networks of evolutionarily conserved DNA damageome proteins (DDPs) promote DNA damage and genome instability. Here, we discovered a lung cancer-associated DNA damageome network. We further discovered that one of the lung cancer DDPs, Aquaporin 3 (AQP3), can promote ROS dependent DNA damage upon overproduction. Furthermore, it potentiates DNA damage by a low dose of arsenic exposure, creating unique double strand break hotspots which help predict mutational signatures. We screened for high endogenous DNA damage levels for more than 40 TWAS and GWAS-nominated candidates using high-throughput single cell-based flow cytometric assays. We optimized and performed Mre11-Cut&Tag (Cleavage Under Targets and Tagmentation) to map double strand breaks, which are the most deleterious form of DNA damage. In addition, we used END-Seq to provide a much higher resolution of the DSB map and uncovered hotspots in arsenic-detoxifying genes. We are implementing duplex sequencing to map the mutational signatures caused by arsenic and the arsenic-Aquaporin 3 interaction. Our study brings function to endogenous DNA damage and DNA damageome proteins that interact with environmental toxicants. Mechanistic insights into how low-dose arsenic interacts with risk genes yield critical knowledge for the prevention, diagnosis, and treatment of arsenic-associated diseases. We also uncovered several early biomarkers to potentially predict the long-term health impacts of arsenic. Citation Format: Jun Xia, Mu Lin, Zhuoyi Song, Gail Fernandes, Susan Rosenberg, Chris Amos. Lung cancer associated DNA Damageome reveals a genome destabilizing role of Aquaporin 3 [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A018.