Abstract 1417: Multiple gastric cancer and predisposing genes
Authors: Wang Anqiang , Li Zhongwu , Ji Xin , Fu Tao , Wu Xiaojiang , Zhang Ji , Bu Zhaode , Ji Jiafu 
Published: August 2019

BACKGROUND: Multiple gastric cancer (MGC) is one special type of gastric cancer with more than two different tumors at various locations of stomach. However, the clonal relationship and carcinogenesis of MGC are still remain unclear. Therefore, we investigated the clonal relationship and role of germline mutations playing in the carcinogenesis of MGC.

METHODS: We collected 16 multiple gastric cancer patients who underwent subtotal and total gastrectomy at Peking Cancer Hospital form January 2016 to December 2017. Thirty-three tumor samples and sixteen normal gastric tissue or blood samples were obtained for experiment. We also conducted analysis for 208 gastric cancer and 49 esophagogastric junction cancer (GC-EGJ) tumors from TCGA. DNA extraction from our samples was conducted for whole exome sequencing. We analyzed nonsynonymous mutations and somatic copy number variations (CNVs) based on exome data. Driver mutations, germline and cancer predisposing genes, significantly mutated genes (SMGs) were also analyzed.

RESULTS: Tumor mutation burden (TMB) was not statically significant within database and our data in GCs-EGJ groups (P=0.0591). And the TMB level was also similar between two databases in GCs groups (P=0.3113). The mutation spectrum and mutation signatures also showed uniform distributions in GCs and GCs-EGJ groups within our data and TCGA database. Among sixteen patients, four were identified as monoclonal, in which 11, 10, 26 and 6 somatic mutations were shared within different tumors of P7, P8, P9 and P16 respectively. However, no common mutation between different tumors of same patient was found from the other 12 patients in spite of thousands of somatic mutations in P2. After identifying predisposing genes, we found that germline MSH2 and NCOR2 mutations were significantly dominant in 8/12 and 10/12 of genetic MGCs patients. And all patients were identified MSH2 mutations in cancer samples of those same patients. Interestingly, the NCOR2 mutations were not detected significantly with non-frameshift INDELs in only three patients. Taking genetic MGCs as a whole, we identified that TP53 were significantly mutated in 14 of 25 tumor samples. And MSH2 mutations were found in all patients. The correlation analysis between clinical information and mutation signatures showed that the signature B was associated with the level of CA72.4.

CONCLUSIONS: Whole exome sequencing analyses are suggestive of monoclonal and polyclonal origin of MGC, which may promote the classification MGC into genetic and metastatic MGC. For genetic MGC patients, germline MSH2 mutations may contribute to the carcinogenesis of them, may thus giving rise to the consideration of more radical surgery and PD-1/PD-L1 therapy.

Citation Format: Anqiang Wang, Zhongwu Li, Xin Ji, Tao Fu, Xiaojiang Wu, Ji Zhang, Zhaode Bu, Jiafu Ji. Multiple gastric cancer and predisposing genes [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 1417.