Abstract 3177: KRAS gene status in gastric signet-ring cell carcinoma patients and act as biomarker of MEK inhibitor

Abstract

Abstract Background: Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer-related death, particularly in China. Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer. Mutations in KRAS are detected in many types of human tumors and have been proved to be associated with development and progression of cancer. In this study, we sought to explore the role of KRAS in signet-ring cell carcinoma. Patients and methods: Genomic data from 393 GC samples from The Cancer Genome Atlas (TCGA) was extracted to analyze mutation status of KRAS. Sanger sequencing for KRAS was applied in 234 FFPE SRCC patient samples. Immunohistochemical(IHC) and Fluorence in situ hybridization(FISH) were performed to detect KRAS expression level and KRAS amplification status in FFPE samples. Patients were evaluated in terms of survival and clinicopathological characteristics, as well as KRAS mutation and expression status in TCGA and in our cohort, respectively. We also explored KRAS mutation and expression level in 4 SRCC cell lines. Drug inhibition rate of MEK/mTOR inhibitors was evaluated by cell viability assay. Results: Thirty-one patients (0.079%) and thirty-seven GC patients (0.094%) in TCGA harbored point mutations and copy number variation (CNV), respectively. Patients with KRAS point mutations and CNV showed higher mRNA level compared to non-mutant cases (P = 0.003 and P < 0.001). No survival difference was observed between KRAS different gene status in TCGA cohort. In our 234 in-house SRCC samples, 15 samples harbored KRAS mutations. We further did analysis on the 75 patients which had enough FFPE samples. Eight patients showed KRAS mutations and two patients showed KRAS amplification. The median overall survival (OS) was 12.5 months for patients with KRAS mutation, and 19.5 months for patients without KRAS mutation (P = 0.045). The majority of SRCC patients are positive with KRAS detected by IHC, which is higher than our intestinal cohort (80% vs 38.6%, P<0.001). However, no difference of overall survival was observed between different KRAS expression level. We further explore the correlation between KRAS status and drug sensitivity in 4 SRCC cell lines. SNU601 and SNU668, which harbored KRAS mutation, were hypersensitive to MEK inhibition. However, mTOR inhibitor showed no preference on SRCC cell lines in terms of KRAS status. Conclusion: These data demonstrate the status of KRAS gene in SRCC and uncover the therapeutic potential for targeting of these tumors through MEK inhibition in SRCC. Citation Format: Nandie Wu, Ying Huang, Xiangshan Fan, Yang Yang, Qin Liu, Lixia Yu, Rafael Rosell, Baorui Liu, Jia Wei. KRAS gene status in gastric signet-ring cell carcinoma patients and act as biomarker of MEK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3177.