Abstract
Esophageal adenocarcinoma (EAC) is associated with a marked genomic instability, which underlies disease progression and development of resistance to treatment. In this study, we used an integrated genomics approach to identify a genomic instability signature. Here we show that elevated expression of this signature correlates with poor survival in EAC as well as three other cancers. Knockout and overexpression screens establish the relevance of these genes to genomic instability. Indepth evaluation of three genes (TTK, TPX2 and RAD54B) confirms their role in genomic instability and tumor growth. Mutational signatures identified by whole genome sequencing and functional studies demonstrate that DNA damage and homologous recombination are common mechanisms of genomic instability induced by these genes. Our data suggest that the inhibitors of TTK and possibly other genes identified in this study have potential to inhibit/reduce growth and spontaneous as well as chemotherapy-induced genomic instability in EAC and possibly other cancers.
Highlights
Esophageal adenocarcinoma (EAC) is associated with a marked genomic instability, which underlies disease progression and development of resistance to treatment
Using EAC and MM as model systems, we previously showed that dysregulated homologous recombination (HR) significantly contributes to genomic instability[14,16], development of drug resistance[16], and tumor growth[17]
As genomic instability is associated with cancer progression and some of the mechanisms of genomic instability are required for tumor growth, we hypothesized that if elevated expression of a gene correlates with increased genomic instability and poor survival in EAC patients, it could be a potential driver of genomic evolution
Summary
Esophageal adenocarcinoma (EAC) is associated with a marked genomic instability, which underlies disease progression and development of resistance to treatment. We used an integrated genomics approach to identify mediators of genomic instability in EAC Functional significance of these genes was confirmed in knockout and overexpression screens. We demonstrate that genes identified in this study and their inhibitors (such as TTK inhibitor used in this study) have the potential to inhibit/reduce genomic instability and growth of cancer cells in vitro and in vivo. Such inhibitors have the potential to reduce chemotherapy-induced genomic instability, while increasing their cytotoxicity
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