Expression profiling and long lasting responses to chemotherapy in metastatic gastric cancer

Current palliative chemotherapy (CT) regimens achieve clinical benefits in less than 50% of patients treated for metastatic gastric cancers, and long-term survivals are anecdotical. Genetic polymorphisms and differences at the level of transcription in genes involved in biological processes of drug metabolism, DNA repair and drug resistance can explain the observed individual differences in response to drugs, in survival and in different susceptibility to the toxic effects of CT. The possibility to classify patients on the basis of genetic signatures could help in choosing the CT regimen. We present herein an analysis of genetic and expression profiling of three patients affected by metastatic gastric cancer, treated with CT and alive, disease-free, at 66-82 months. Four patients with typical clinical outcome represented the control group. Expression profiling from paraffin-embedded tumor tissues was performed on an ad hoc set of genes involved in drug metabolism and resistance, DNA repair, cell cycle regulation and growth factors signalling. Genetic polymorphism analysis on DNA extracted from peripheral blood was done by pyrosequencing of genetic markers predictive of drug response. Expression analysis in long-term survivors revealed a significant upregulation of PTEN, TP63, GADD45a and MAPK1 genes. We found also an upregulation of CYP1A1, CYP3A4 and ERBB4 genes. EGF was found to be down-regulated in long-term survivors. ERCC1 C8092A polymorphism seems to be associated with survival in our set of patients. The present study shed light on a set of genes, which could have a predictive role in survival of patients with metastatic gastric tumors.