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BACKGROUND AND AIMS Purpose of this study was to identify drivers of genomic evolution in esophageal adenocarcinoma (EAC) and other solid tumors. METHODS An integrated genomics strategy was used to identify deoxyribonucleases correlating with genomic instability (as assessed from total copy number events in each patient) in six cancers. Apurinic/apyrimidinic nuclease 1 (APE1), identified as top gene in functional screens, was either suppressed in cancer cell lines or overexpressed in normal esophageal cells, and impact on genome stability and growth monitored in vitro and in vivo. Impact on DNA/chromosomal instability was monitored using multiple approaches including investigation of micronuclei, acquisition of single nucleotide polymorphisms, whole genome sequencing (WGS) and/or multicolor fluorescence in situ hybridization. RESULTS Expression of four deoxyribonucleases correlated with genomic instability in six human cancers. Functional screens of these genes identified APE1 as top candidate for further evaluation. APE1-suppression in EAC, breast, lung and prostate cancer cell lines caused: 1) Cell cycle arrest; 2) Impaired growth and increased cytotoxicity of cisplatin in all cell lines/types and in mouse model of EAC; 3) inhibition of homologous recombination (HR) and spontaneous and chemotherapy-induced genomic instability. APE1-overexpression in normal cells caused a massive chromosomal instability leading to their oncogenic transformation. Evaluation of these cells by WGS demonstrated the acquisition of changes throughout genome and identified HR as the top mutational process. CONCLUSIONS Elevated APE1 dysregulates HR and cell cycle contributing to genomic instability, tumorigenesis and chemoresistance, and its inhibitors have potential to target these processes in EAC and possibly other cancers.