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Revista de Gastroenterologia de Mexico... 2023
Topics: Humans; Linitis Plastica; Stomach Neoplasms
PubMed: 37208213
DOI: 10.1016/j.rgmxen.2023.05.005 -
Comprehensive transcriptomic profiling and mutational landscape of primary gastric linitis plastica.Gastric Cancer : Official Journal of... Mar 2023Primary gastric linitis plastica (GLP) is a distinct phenotype of gastric cancer with poor survival. Comprehensive molecular profiles and putative therapeutic targets of...
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.
Topics: Humans; Linitis Plastica; Stomach Neoplasms; Transcriptome; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Mutation; Protein Tyrosine Phosphatases, Non-Receptor; Carrier Proteins
PubMed: 36450891
DOI: 10.1007/s10120-022-01353-2 -
Canadian Medical Association Journal Sep 1914
PubMed: 20310533
DOI: No ID Found -
Annals of Surgery May 1921
PubMed: 17864459
DOI: 10.1097/00000658-192105000-00005 -
World Journal of Surgical Oncology Jul 2017Linitis plastica due to gastric adenocarcinoma is a condition with a long history, but still lacks a standardized definition and is commonly confused with Borrmann type... (Review)
Review
BACKGROUND
Linitis plastica due to gastric adenocarcinoma is a condition with a long history, but still lacks a standardized definition and is commonly confused with Borrmann type IV, Lauren diffuse, and signet-cell type gastric cancer. The absence of a clear definition is a problem when investigating its biological characteristics and role as a possible independent factor for prognosis. Nevertheless, the biological behavior for linitis plastica, which is unique, may be valuable in risk stratification and have implications for treatment. A definition of linitis plastica based on molecular or genomic criteria could represent a useful starting point for investigating new targeted therapies.
MAIN BODY
This literature review of linitis plastica will focus on the current classifications for gastric cancer, illustrating how the concept of linitis plastica relates to them in most cases and identifying a clear and reproducible definition. Moreover, the review will highlight the diagnostic challenges associated with linitis plastica, its prognostic implications, and the therapeutic options available. Future perspectives for its management are also addressed.
CONCLUSION
Linitis plastica is a carcinoma with a scirrhous stroma, involving the submucosal and muscular layers of the stomach even in the absence of mucosal alteration. In most cases, the primary cancer cells are signet-ring cells or scattered cells in the context of a poorly differentiated carcinoma. Diagnosis is challenging. Staging should be thorough, including diagnostic laparoscopy in all cases due to the high incidence of peritoneal involvement. The prognostic significance of linitis plastica is still controversial. Curative-intent surgery, when feasible, should be performed, with a multimodality treatment approach. Cancer-stroma interactions are important features of this disease, and represent attaining potential target for future therapies. Future pathologic assessments of gastric cancer should report the stromal reaction in order to allow better characterization of the tumor.
Topics: Adenocarcinoma; Genetic Markers; Genomics; Humans; Linitis Plastica; Prognosis; Stomach Neoplasms
PubMed: 28679451
DOI: 10.1186/s12957-017-1187-3 -
Molecular Oncology Aug 2023The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole-exome sequencing...
The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole-exome sequencing (WES) and T-cell receptor (TCR) sequencing on 40 tumor regions from four LP patients. The landscape and ITH at the genomic and immunological levels in LP tumors were compared with multiple cancers that have previously been reported. The lymphocyte infiltration was further assessed by immunohistochemistry (IHC) in LP tumors. In total, we identified 6339 non-silent mutations from multi-samples, with a median tumor mutation burden (TMB) of 3.30 mutations per Mb, comparable to gastric adenocarcinoma from the Cancer Genome Atlas (TCGA) cohort (P = 0.53). An extremely high level of genomic ITH was observed, with only 12.42%, 5.37%, 5.35%, and 30.67% of mutations detectable across 10 regions within the same tumors of each patient, respectively. TCR sequencing revealed that TCR clonality was substantially lower in LP than in multi-cancers. IHC using antibodies against CD4, CD8, and PD-L1 demonstrated scant T-cell infiltration in the four LP tumors. Furthermore, profound TCR ITH was observed in all LP tumors, with no T-cell clones shared across tumor regions in any of the patients, while over 94% of T-cell clones were restricted to individual tumor regions. The Morisita overlap index (MOI) ranged from 0.21 to 0.66 among multi-regions within the same tumors, significantly lower than that of lung cancer (P = 0.002). Our results show that LP harbored extremely high genomic and TCR ITH and suppressed T-cell infiltration, suggesting a potential contribution to the frequent recurrence and poor therapeutic response of this adenocarcinoma.
Topics: Humans; Linitis Plastica; Stomach Neoplasms; Exome Sequencing; Genetic Heterogeneity; Genes, T-Cell Receptor; Tumor Microenvironment; Mutation
PubMed: 36703611
DOI: 10.1002/1878-0261.13381 -
International Journal of Molecular... Sep 2023Linitis Plastica (LP) is a rare and aggressive tumor with a distinctive development pattern, leading to the infiltration of the gastric wall, the thickening of the... (Review)
Review
Linitis Plastica (LP) is a rare and aggressive tumor with a distinctive development pattern, leading to the infiltration of the gastric wall, the thickening of the gastric folds and a "leather bottle appearance". LP is an extremely heterogeneous tumor caused by mutations in oncogenic and tumor suppressive genes, as well as molecular pathways, along with mutations in stromal cells and proteins related to tight junctions. Elucidating the molecular background of tumorigenesis and clarifying the correlation between cancerous cells and stromal cells are crucial steps toward discovering novel diagnostic methods, biomarkers and therapeutic targets/agents. Surgery plays a pivotal role in LP management, serving both as a palliative and curative procedure. In this comprehensive review, we aim to present all recent data on the molecular background of LP and the novel approaches to its management.
Topics: Humans; Linitis Plastica; Stomach Neoplasms; Genomics
PubMed: 37834127
DOI: 10.3390/ijms241914680 -
Endoscopic Ultrasound 2020
PubMed: 32584317
DOI: 10.4103/eus.eus_20_18