Comprehensive transcriptomic profiling and mutational landscape of primary gastric linitis plastica

作者：Zhu Liu, Lian‐Lian Hong, Jinsen Zheng, Zhenan Ling, Zhe-Nan Ling, Zhilong Zhang, Yanan Qi, Xinyu Zhang, Tianyu Zhu, Jiu-Li Wang, Jing Han, Xiang-Liu Chen, Qi-Ming Yu, Shi Wang, Zhi‐Qiang Ling, Zhi‐Qiang Ling, Zhi‐Qiang Ling · 发表于：Gastric Cancer · 年份：2022 · DOI：10.1007/s10120-022-01353-2 · 被引用次数：13 · 研究领域：Hippo pathway signaling and YAP/TAZ、Hedgehog Signaling Pathway Studies、Kruppel-like factors research

BACKGROUND: Primary gastric linitis plastica (GLP) is a distinct phenotype of gastric cancer with poor survival. Comprehensive molecular profiles and putative therapeutic targets of GLP remain undetermined. METHODS: We subjected 10 tumor-normal tissue pairs to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). 10 tumor samples were all GLP which involves 100% of the gastric wall macroscopically. TCGA data were compared to generate the top mutated genes and the overexpressed genes in GLP. RESULTS: Our results reveal that GLP has distinctive genomic and transcriptomic features, dysfunction in the Hippo pathway is likely to be a key step during GLP development. 6 genes were identified as significantly highly mutated genes in GLP, including AOX1, ANKRD36C, CPXM1, PTPN14, RPAP1, and DCDC1). MUC6, as a previously identified gastric cancer driver gene, has a high mutation rate (20%) in GLP. 20% of patients in our GLP cohort had CDH1 mutations, while none had RHOA mutations. GLP exhibits high immunodeficiency and low AMPK pathway activity. Our WTS results showed that 3 PI3K-AKT pathway-related genes (PIK3R2, AKT3, and IGF1) were significantly up-regulated in GLP. Two genes were identified using immunohistochemistry (IHC), IGF2BP3 and MUC16, which specifically expressed in diffuse-type-related gastric cancer cell lines, and its knockdown inhibits PI3K-AKT pathway activity. CONCLUSIONS: We provide the first integrative genomic and transcriptomic profiles of GLP, whi...