| Summary: | The majority of gastric cancer (GC) patients present at advanced stage and have a poor prognosis. Poor survival might be related to the unavailability of molecular markers to determine patient management. Most GC are considered genetically unstable (microsatellite unstable (MSI)) and/or chromosomal unstable (CIN). Recent studies suggest that CIN cancers are multi-drug resistant. First drugs targeting specific characteristics of CIN cancer have shown activity in vitro. Thus, there is an urgent need to fully understand the mechanisms leading to and maintaining CIN in GC as this might identify new treatment targets. It has been proposed that CIN might be caused by an impaired DNA damage response (DDR). The current study characterised the type of genetic instability present in GC measuring DNA ploidy (CIN surrogate marker) as well as MSI and investigated in parallel the expression of all key DDR proteins and their downstream signalling pathways regulating cell cycle progression in a retrospectively collected series of GC using immunohistochemistry and tissue microarray technology. GC were also screened for KRAS and BRAF mutations as the RAS signalling pathway had been implicated in generating genetic instability in colorectal cancer. This is the first study to identify a significant overlap between MSI and CIN in a subset of GC with poor prognosis. DNA double strand breaks were rare in GC making deregulated DNA damage response unlikely as the major mechanism leading to CIN in GC. The identification of GC with low proliferative index, low DNA repair activity and poor survival suggested that a subset of GC may switch from proliferation to invasion, identifying a potential additional cause for GC resistance against cytotoxic drugs warranting further studies. KRASIBRAF mutations were rare in GC, related to MSI but not to CIN. Results from this exploratory study require and warrant validation in a larger independent cohort.
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