Targeted-sequencing and comprehensive molecular profiling of gastric signet ring cell carcinoma.

e16065 Background: Gastric cancer is a heterogeneous disease with various molecular subtypes. Signet ring cell carcinoma is characterized by a highly malignant phenotype of gastric cancer with few known effective molecularly targeted therapies. The limited knowledge of the molecular mechanisms underlying signet ring cell carcinoma hinders the development of therapeutic strategies. Methods: We performed a targeted sequencing panel focusing on 416 genes in 70 gastric signet ring cell carcinoma (SRCC) tumor-normal pairs, for integrative genomic analysis. This gene panel is composed of 416 cancer-related genes which can test a wide range of genetic abnormalities including point mutations, fusions, insertions, deletions and amplifications. Furthermore, this panel covers all currently available molecular-targeted and chemotherapy drugs, and ongoing clinical trials. Results: We identified previously well-known oncogenes and tumor suppressor genes mutation, including chromatin remodeling genes CDH1(17%), ARID1A(9%), BRCA1 (6%), CHD4(6%), SMARCA4(4%), TP53(27%)dysregulation, activation of receptor tyrosine kinases genes ERBB3(9%), PIK3CA(7%), PTEN (6%), MTOR(4%), ERBB2(4%), ERBB4(3%), FGFR2(3%), FGFR4(3%), stem cell pathways genes TGFBR2(6%), APC(3%), and others. Meanwhile, we observed new significantly mutated genes in SRCC. Specifically, gene PKHD1(16%), MED12(16%), STAG2(10%), KDR (10% ), ATRX(9%) were frequently mutated in SRCC tumor samples. However, RHOA mutation was detected only in 4% tumor samples. For DNA copy number profiling, genes including NOTCH1(16%), FLT4(9%), CCND1 (7%), HNF1A(6%), CDKN2A(6%), CDKN2B(6%) and RECQL4(6%), were frequently altered in SRCC. Conclusions: Our genomic landscape revealed SRCC was a distinct entity which harboring different mutational profile to other gastric cancers. Our results may provide potential target for genome-guided personalized therapy in SRCC.