Genomic and transcriptomic landscape of carcinogenesis in patients with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)
Abstract
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal dominant syndrome characterized by polyposis localized in the gastric body and fundus with a strong tendency for adenocarcinoma. The genetic mutations that accumulate during the progression from normal mucosa through polyp to carcinoma in GAPPS remain unclear. We investigated the evolutionary process from normal mucosa to polyp and carcinoma in GAPPS. Through comprehensive mutational and transcriptome analyses, we aimed to provide insights into the biology of this disease. Whole-exome sequencing and RNA sequencing were performed on carcinoma, polyp, and normal mucosa samples from multiple sites from seven patients with GAPPS (n = 54 samples). We comprehensively investigated genomic alterations (including copy number alterations and somatic mutations), clonal architecture, and transcriptome dynamics during carcinogenesis. Genomic evolutionary analysis showed that in GAPPS, somatic mutations of APC occur in carcinoma and polyp while mutations of KRAS additionally occur in carcinoma. We also found the co-occurrence of APC and KRAS mutations in carcinoma recurrently both across cases and within subclones of the same case. The co-occurrence of APC/KRAS mutations may contribute to the carcinogenesis of GAPPS. Our study provides detailed information on the genomic and transcriptomic landscape in GAPPS carcinogenesis, conferring valuable insights into its underlying mechanisms.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Chihiro Matsumoto
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University
Kazuki K. Takahashi
Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo
Masaaki Iwatsuki
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University
Noriko Yasuda-Yoshihara
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University
Atsushi Niida
Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo
Kohei Yamashita
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University
Takeshi Morinaga
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University
Kojiro Eto
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University
Shiro Iwagami
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University
Satoshi Ida
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University
Hiromu Yano
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University
Yoshihiro Komohara
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University
Yuji Miyamoto
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University
Takaaki Masuda
Department of Breast and Endocrine Surgery, Kochi University
Yasuhito Tanaka
Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
Koshi Mimori
Department of Surgery, Kyushu University Beppu Hospital
Hideo Baba
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University