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Background  RAS-RAF-MEK-ERK and PI3K-AKT pathways form a significant cascade for potential molecular target therapy in advanced cancer. The clinical significance of mutations in these genes in advanced gastric cancer (AGC) is uncertain.    Methods  We collected formalin-fixed, paraffin-embedded and fresh frozen tumor samples from AGC patients and analyzed the  KRAS, NRAS, BRAF  and  PIK3CA  mutations by direct-sequencing. We retrospectively investigated the clinicopathological features of these mutations in AGC patients, and selected patients with metastatic gastric cancer.    Results  Among 167 AGC patients, mutations of  KRAS  codons 12/13 ( N  = 8/164, 4.9%),  PIK3CA  ( N  = 9/163, 5.5%), and  NRAS  codon 12/13( N  = 3/159, 1.9%) were detected. Comparison of the clinicopathological features of the mutated  KRAS, PIK3CA, NRAS  genes with an all-wild type of these genes showed that the frequency of the intestinal type was significantly higher in patients whose tumor tissue contained  KRAS  mutations ( P  = 0.014). Among 125 patients with metastatic gastric cancer, patients with  NRAS  codon 12/13 mutations in their tumors had shorter overall survival compared with  NRAS  wild-type patients (MST: 14.7 vs 8.8 months,  P  = 0.011). By multivariate analyses,  NRAS  codon 12/13 mutation was an indicator for poor prognosis in patients with metastatic gastric cancer (adjusted HR 5.607, 95% CI: 1.637-19.203).    Conclusions  Our study indicated that mutations of  KRAS, PIK3CA  and  NRAS  were rare in AGC.  NRAS  mutations were likely to associate with poor prognosis in metastatic state of AGC patients, but further validation of other research is required.

Clinicopathological features and prognostic roles of KRAS, BRAF, PIK3CA and NRAS mutations in advanced gastric cancer