Comprehensive transcriptomic profiling and mutational landscape of primary gastric linitis plastica

Abstract

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.

Whole‐transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential

“…Nonetheless, in GC/GEJC, which is considered highly heterogeneous, some of these molecules are difficult to evaluate using IHC or other evaluation methods, and thresholds have not yet been established. In this context, WTS does not fully resolve the complexities of tumor heterogeneity but it may be useful to homogenize the varied expression within a tumor to provide quantitative data, even for samples with strong heterogeneity 16 . More specifically, there may exist subpopulations that, despite receiving negative evaluations through IHC and consequently being disqualified from targeted therapy, demonstrate elevated expression through WTS, which renders them potentially eligible for such treatments.…”

“…In this context, WTS does not fully resolve the complexities of tumor heterogeneity but it may be useful to homogenize the varied expression within a tumor to provide quantitative data, even for samples with strong heterogeneity. 16 More specifically, there may exist subpopulations that, despite receiving negative evaluations through IHC and consequently being disqualified from targeted therapy, demonstrate elevated expression through WTS, which renders them potentially eligible for such treatments. However, few studies have comprehensively evaluated the correlation between IHC and WTS and the contrast in their prognostic impact.…”

CPXM1 correlates to poor prognosis and immune cell infiltration in gastric cancer

“…Recently, researchers performed whole exome sequencing and whole transcriptome sequencing on ten tumor–normal tissue pairs; all were GLPs. Six genes, including CPXM1, were found to have significant high levels of mutation in GLP [ 18 ]. However, it remains unknown how CPXM1 contributes to GC.…”

The Genomic Signatures of Linitis Plastica Signal the Entrance into a New Era: Novel Approaches for Diagnosis and Treatment

“…Gastric cancer (GC) ranks as the fifth most common malignancy worldwide, with approximately 1.1 million new cases annually. It stands out as having one of the highest mortality rates with the third most deaths [1][2][3][4]. Linitis Plastica (LP), a subtype of gastric cancer, constitutes 10% of all GC cases [2,5,6].…”

“…First observed in the 16th and 17th centuries, it was formally described in 1859 by William Brinton [7]. Macroscopically, LP is characterized by the thickening of the gastric folds due to accumulation of fibrous tissue, often referred to as the "Leather-bottle stomach" [3,5,7,8]. The term "Linitis" derives from its "linen-like" macroscopical image.…”