Chronic inflammation is a driving force for gastric carcinogenesis. Reactive oxygen species (ROS) generated during the inflammatory process generates DNA damage that is processed through the DNA repair pathways. In this study, we profiled key DNA repair proteins (single-strand-selective monofunctional uracil-DNA glyco- In the multivariate Cox model, high XRCC1 and low ATM were independently associated with poor survival ( p = 0.008 and 0.011, respectively). Our observation supports the hypothesis that DNA repair factors are promising biomarkers for personalized therapy in gastric cancer.

1016 Background: FEN1 is a multifunctional protein with essential roles in long patch base excision repair (LP-BER), Okazaki fragment maturation during replication, resolution of tri-nucleotide repeat sequence-derived secondary structures, rescue of stalled replication forks, maintenance of telomere stability and apoptotic fragmentation of DNA. In the current study we have evaluated FEN1 as a prognostic, predictive and therapeutic target in BC and OVC. Methods: Clinico-pathological significance of FEN1 mRNA expression was evaluated in a BC training cohort [n=128], test cohort (n=249) and validated in a large cohort of 1,980 BC (METABRIC). Neural network analysis (NNA) was conducted to identify FEN1 interaction genes. FEN1 protein expression was investigated in three consecutive series of BC and OVC: 568 ER negative (ER- BC), 894 ER positive (ER+ BC) and 195 OVC cohorts. Pre-clinically, FEN1 deficient and proficient HeLa cell lines were investigated for chemotherapy sensitization. A high throughput screening (HTS) strategy was developed to identify FEN1inhibitors for therapeutic application. Results: FEN1mRNA overexpression is associated with adverse clinicopathological features such as high grade, high mitotic index, and triple negative (ps<0.0001). High FEN1 mRNA expression was highly significantly associated with PAM50 Her2, PAM50 Basal and PAM50 LumB (ps<0.0001) BC. FEN1 mRNA overexpression is associated with resistance to chemotherapy (p=0.019), endocrine therapy (p<0.0001) and independently with poor survival (p<0.0001). NNA revealed novel interaction genes with predominant roles in proliferation, cell growth, DNA repair, differentiation, invasion, migration, metabolism and apoptosis. FEN1 protein overexpression is significantly associated with aggressive clinico-pathological features and independently with poor survivals in ER+ BC, ER- BC and in OVC (ps<0.001). HTS assay has identified novel FEN1 inhibitors for therapeutic development. Conclusions: This is the first study to investigate FEN1 in BC and OVC. We provide confirmatory evidence that FEN1 is a promising biomarker as well as a therapeutic anti-cancer drug target for clinical application.