gene status in gastric signet-ring cell carcinoma patients and acts as biomarker of MEK inhibitor.

Background: Signet-ring cell carcinoma (SRCC) is a specific subtype of stomach cancer with unique epidemiology. Here, we sought to explore the role of in SRCC.

Methods: status was studied both in The Cancer Genome Atlas (TCGA) and internal cohorts. Immunohistochemistry (IHC) and fluorescence hybridization (FISH) were performed in formalin-fixed and paraffin-embedded (FFPE) samples. We explored patients' survival and clinicopathological characteristics in terms of mutation and expression. We also explored status and drug response curve of MEK/mTOR inhibitors in SRCC cell lines.

Results: Patients with mutations and copy number variation (CNV) showed higher mRNA level compared to non-mutant cases (P=0.003 and P<0.001). In internal cohort, 15 samples harbored mutations. Survival analysis showed that these patients had significantly lower overall survival (OS) (P=0.048). We further analyzed 75 patients with sufficient FFPE samples. Eight patients showed mutations and one patient showed amplification. The median OS was 12.5 months for patients with mutation, and 19.5 months for patients without mutation (P=0.005). Positive expression of as shown by IHC was detected in majority of SRCC samples, which was higher than our intestinal cohort (28% 12.6%, P=0.033). We further explored the correlation between status and drug sensitivity in 4 SRCC cell lines. SNU601 and SNU668, which harbored mutation, were hypersensitive to MEK and mTOR inhibitors than wide type cell lines KATO-III and NUGC-4.

Conclusions: Our findings demonstrate that gene plays an important role in SRCC and reveals therapeutic potential of targeting tumors by inhibiting MEK and mTOR pathways.