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Unveiling DNA damage repair-based molecular subtypes, tumor microenvironment and pharmacogenomic landscape in gastric
Weiqi Kong1, Zhiqiang Wang1, Bingyi Wang1
1Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Objective: The current molecular classification system for gastric cancer covers genomic, molecular, and morphological characteristics. Non-etheless, classification of gastric cancer based upon DNA damage repair is still lacking. Here, we defined DNA damage repair-based subtypes across gastric cancer and identified clinicopathological, tumor microenvironment and pharmacogenomic features. Methods: Unsupervised clustering analysis was executed in the TCGA-STAD cohort based upon the transcriptional expression profiling of DNA damage repair genes. LASSO computational approach was adopted for generating a DNA damage repair-relevant gene signature. The identified subtypes or signature were externally verified in the GSE84426 or GSE84433 cohort. The transcriptional levels of immunomodulators, abundance of immune cells and somatic mutations were measured, respectively. Immunotherapeutic response, and drug sensitivity were investigated. The DNA damage repair-relevant genes were further experimentally verified. Results: Two DNA damage repair-based subtypes were identified, with the notable heterogeneity in prognostic stratification, tumor microenvironment and somatic mutations. The gene signature was generated for risk stratification and prognostic prediction, which was in relation to immunomodulators and immune cells. High-risk cases were more likely to respond to immunotherapy, with distinct pharmacogenomic landscapes between low- and high-risk groups. Higher levels of PAPPA2, MPO, MAGEA11, DEPP1, CPZ, and COLEC12 and lower level of CYTL1 were proven in gastric cancer cells versus controls. Silencing CYTL1 facilitated intracellular ROS accumulation and suppressed migration in gastric cancer cells. Conclusion: Collectively, the DNA damage repair-based classification is a suitable complement to existing molecular classification system, and the quantitative gene signature provides a robust tool in selecting specific therapeutic options.
Insights
This study defines new DNA damage repair subtypes for gastric cancer, identifying a gene signature that predicts prognosis and response to immunotherapy. This classification complements existing systems for personalized treatment selection.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastric cancer classification lacks subtypes based on DNA damage repair mechanisms.
- Existing systems focus on genomic, molecular, and morphological features.
Purpose of the Study:
- To define DNA damage repair-based subtypes of gastric cancer.
- To identify clinicopathological, tumor microenvironment, and pharmacogenomic features associated with these subtypes.
- To develop a gene signature for risk stratification and prognostic prediction.
Main Methods:
- Unsupervised clustering of DNA damage repair gene expression in the TCGA-STAD cohort.
- LASSO regression for gene signature development.
- External validation of subtypes and signature.
- Analysis of immunomodulators, immune cells, somatic mutations, and drug sensitivity.
- Experimental verification of key DNA damage repair genes.
Main Results:
- Two distinct DNA damage repair subtypes were identified with significant heterogeneity in prognosis, tumor microenvironment, and somatic mutations.
- A gene signature was developed for risk stratification, correlating with immunomodulators and immune cells.
- High-risk patients showed better response to immunotherapy and distinct pharmacogenomic profiles.
- Specific gene expression differences (e.g., CYTL1) were validated in gastric cancer cells.
Conclusions:
- DNA damage repair-based classification offers a valuable complement to current gastric cancer molecular subtypes.
- The developed gene signature serves as a robust tool for guiding therapeutic decisions and predicting treatment response.
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