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Theranostics 2020; 10(12):5489-5500. doi:10.7150/thno.42814 This issue Cite

Research Paper

Molecular characteristics of synchronous multiple gastric cancer

Anqiang Wang^1#, Zhongwu Li^2#, Meng Wang^3#, Shuqin Jia^4#, Jiahu Chen¹, Ke Ji¹, Xin Ji¹, Xianglong Zong¹, Xiaojiang Wu¹, Ji Zhang¹, Ziyu Li¹, Lianhai Zhang¹, Ying Hu⁵, Zhaode Bu^1✉, Qi Zheng^3✉, Jiafu Ji^1✉

1. Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
2. Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
3. Novogene Bioinformatics Technology Co., Ltd, Beijing 100083, China
4. Center for Molecular Diagnostics, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
5. Department of Biobank, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing 100142, China
#These authors contributed equally to this study.

✉ Corresponding authors: Jiafu Ji, MD, PhD, Department of Gastrointestinal Surgery Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China. Tel: 86-10-88196970, Fax: 86-10-88196970, Email: jijiafupku.edu.cn. Qi Zheng, PhD, Novogene Bioinformatics Technology Co., Ltd, Beijing 100083, China. Tel: 86-10-88196970, Fax: 86-10-88196970, Email: zhengqicom. Zhaode Bu, MD, Department of Gastrointestinal Surgery Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China. Tel: 86-10-88196970, Fax: 86-10-88196970, Email: buzhaodeorg More

Abstract

Rationale: Multiple gastric cancer (MGC) is characterized by the presence of more than two different tumors in the stomach. However, the clonal relationship and carcinogenesis of MGC remain unclear. We investigated the clonal relationship and role of germline mutations in the carcinogenesis of MGC.

Methods: We gathered 16 multiple gastric cancer patients. Thirty-three tumor samples and sixteen normal gastric tissue or blood samples were obtained from January 2016 to December 2017. We also conducted analyses 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 (WES).

Results: Tumor mutation burden (TMB) was not statistically significant within database and our data in the GC-EGJ (P=0.0591) and GC groups (P=0.3113). The mutation spectrum and signatures also showed uniform distributions in GC and GC-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 the same patient was found among the other 12 patients. After identifying predisposing genes, we found that germline MSH2 and NCOR2 mutations were significantly dominant in 8/12 and 10/12 of genetic MGC patients. Additionally, all patients were identified with MSH2 mutations in cancer samples of those genetic MGC patients. Taking genetic MGCs as a whole, we identified that TP53 were significantly mutated in 14 of 25 tumor samples.

Main conclusions: WES analyses are suggestive of monoclonal and polyclonal origin of MGC, which may promote the classification of MGC into genetic and metastatic MGC. For patients with genetic MGC, germline MSH2 X314_splice variants may contribute to carcinogenesis, thus prompting the consideration of more radical surgery and/or anti-PD-1/PD-L1 therapy.

Keywords: Multiple gastric cancer, whole-exome sequencing, clonal relationship, MSH2 gene, predisposing gene, TCGA

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