Molecular alterations in claudin 18 suppressed and non-suppressed gastric adenocarcinomas to guide targeted therapies
1Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, Ontario, Canada.
Background:
Gastric adenocarcinoma represents an aggressive type of cancer and an important cause of cancer mortality. Progress in gastric cancer therapeutics has resulted from a better understanding of the molecular pathogenesis of the disease and introduction of targeted therapies, but most gastric cancer patients still rely on non-targeted chemotherapy as the mainstay of treatment for advanced disease.
Methods:
An analysis of publicly available series from The Cancer Genome Atlas (TCGA) gastric cancer cohort was undertaken to delineate the clinical and genomic landscape of gastric cancers with suppressed expression of claudin 18 compared with cancers with non-suppressed claudin 18. Claudin 18 suppressed cancers were defined as having an mRNA expression z-score relative to normal samples (log RNA Seq V2) of less than -1. Claudin 18 non-suppressed cancers were defined as having an mRNA expression z-score relative to normal samples (log RNA Seq V2) above 0.5.
Results:
Gastric cancers with claudin 18 mRNA suppression represented 7.7% of the gastric adenocarcinomas of TCGA cohort, while non-suppressed cancers represented 46.6% of the cases. The two groups did not differ in clinical and genomic characteristics, such as mean age, histology, grade, and stage. The mutation landscape of claudin 18 suppressed cases included high mutation rates of TP53, of genes of the WNT/β-catenin pathway and of ubiquitin ligase FBXW7. Moreover, a subset of both claudin 18 suppressed and non-suppressed cancers displayed mutations in Mismatch Repair (MMR) associated genes or a high tumor mutation burden (TMB). At the mRNA expression level, claudin 18 suppressed gastric cancers showed up-regulation of EMT core transcription factor Snail 2 and down-regulation of genes of HLA cluster. The survival of gastric cancer patients with claudin 18 mRNA suppression was not significantly different compared with patients with non-suppressed claudin 18.
Conclusion:
Sub-sets of gastric cancers with claudin 18 mRNA suppression displayed characteristics of potential therapeutic interest, such as mutations in WNT and PI3K pathways and MMR defects. These may guide the development of alternative targeted therapies, in this sub-set of gastric cancers which are not candidates for claudin 18 targeting therapies.
Insights
Gastric cancers with suppressed claudin 18 expression show distinct molecular features, including mutations in WNT and PI3K pathways. These findings may inform targeted therapy development for a subset of patients.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Gastric adenocarcinoma is an aggressive cancer with high mortality.
- Current treatments for advanced disease primarily rely on non-targeted chemotherapy.
- Targeted therapies offer promise but require deeper understanding of molecular drivers.
Purpose of the Study:
- To analyze the clinical and genomic landscape of gastric cancers with suppressed claudin 18 expression.
- To compare these features with gastric cancers having non-suppressed claudin 18.
- To identify potential therapeutic targets in claudin 18 suppressed gastric cancers.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) gastric cancer cohort.
- Comparison of gastric cancers with suppressed claudin 18 mRNA expression (z-score < -1) versus non-suppressed (z-score > 0.5).
- Evaluation of clinical characteristics, genomic mutations, and mRNA expression profiles.
Main Results:
- Gastric cancers with claudin 18 suppression represented 7.7% of the TCGA cohort.
- No significant differences in clinical characteristics (age, histology, grade, stage) were observed between groups.
- Suppressed claudin 18 cancers showed high mutation rates in TP53, WNT/β-catenin pathway genes, and FBXW7, with altered EMT and HLA gene expression.
Conclusions:
- Subsets of claudin 18 suppressed gastric cancers exhibit mutations in WNT and PI3K pathways and Mismatch Repair (MMR) defects.
- These molecular alterations suggest potential for alternative targeted therapies.
- This research may guide the development of novel treatments for gastric cancer patients not eligible for claudin 18 targeting therapies.
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