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Comprehensive transcriptomic profiling and mutational landscape of primary gastric linitis plastica

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...

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Detalles Bibliográficos
Autores principales: Liu, Zhu, Hong, Lian-Lian, Zheng, Jin-Sen, Ling, Zhe-Nan, Zhang, Zhi-Long, Qi, Ya-Nan, Zhang, Xin-Yu, Zhu, Tian-Yu, Wang, Jiu-Li, Han, Jing, Chen, Xiang-Liu, Yu, Qi-Ming, Wang, Shi, Li, Pei, Ling, Zhi-Qiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Nature Singapore 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9950178/
https://www.ncbi.nlm.nih.gov/pubmed/36450891
http://dx.doi.org/10.1007/s10120-022-01353-2
Descripción
Sumario: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, which may facilitate its diagnosis, prognosis, and treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10120-022-01353-2.