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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Identification of therapeutic targets in lung adenocarcinoma using Mendelian randomization and multi-omics
1Department of Respiratory Medicine, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, No. 26 of Heping Road, Xiangfang District, Harbin, 150040, China.
Background:
Lung adenocarcinoma (LUAD) remains associated with limited effective pharmacological treatment options. This study aimed to identify potential therapeutic targets for LUAD through the integration and analysis of multi-omics datasets.
Methods:
A meta-analysis was conducted using two extensive proteomics datasets, the UK Biobank Proteomics Project (UKB-PPP) and the Fenland study, to identify disease-associated targets for LUAD through the Summary-Data-Based Mendelian Randomization method. Sensitivity analysis, including heterogeneity tests for dependent instruments, were conducted to validate the findings. The prognostic relevance of the identified candidate targets was assessed using transcriptomic data. Functional interactions were explored via protein-protein interaction network analysis, while single-cell analyses were employed to determine cell-specific expression patterns and differentiation trajectories. Potential side effects and therapeutic indications of these targets were evaluated using phenome-wide association studies and pharmacological data mining.
Results:
Following meta-analysis, a primary significant target, intercellular adhesion molecule 5 (ICAM5), along with potential targets FUT8 and KLK13, were identified as therapeutic candidates for LUAD. FUT8 demonstrated a positive association with LUAD risk (OR = 1.02, p = 0.049), while ICAM5 (OR = 0.88, p = 0.002) and KLK13 (OR = 0.85, p = 0.021) exhibited negative associations. ICAM5 was further identified as an independent prognostic factor for patient survival (HR: 0.788, 95% CI: 0.663-0.936, p = 0.007) and revealed significant diagnostic and prognostic utility in LUAD. ICAM5 expression correlated with various immune infiltration patterns, suggesting potential modulation of the tumor immune microenvironment. Single-cell analysis revealed that ICAM5 did not directly impact LUAD cell differentiation, though its downstream target, MUC1, may contribute to differentiation processes, particularly in KRAS-mutated LUAD. Furthermore, phenome-wide association studies did not reveal substantial evidence of adverse phenotypes linked to ICAM5, supporting its safety profile for drug development.
Conclusion:
ICAM5 emerges as a promising biological marker with significant prognostic and therapeutic potential in LUAD.
Insights
Intercellular adhesion molecule 5 (ICAM5) shows promise as a therapeutic target for lung adenocarcinoma (LUAD). This study identified ICAM5 as a prognostic factor and potential therapeutic agent with a favorable safety profile for LUAD treatment.
Area of Science:
- Oncology
- Genomics
- Proteomics
Background:
- Lung adenocarcinoma (LUAD) presents limited pharmacological treatment options.
- Identifying novel therapeutic targets is crucial for improving LUAD patient outcomes.
Purpose of the Study:
- To identify potential therapeutic targets for LUAD using integrated multi-omics data analysis.
- To evaluate the prognostic and therapeutic potential of identified LUAD targets.
Main Methods:
- Meta-analysis of proteomics data (UKB-PPP, Fenland) using Summary-Data-Based Mendelian Randomization.
- Prognostic assessment using transcriptomic data and survival analysis.
- Exploration of functional interactions, cell-specific expression, and potential side effects via network analysis, single-cell studies, and phenome-wide association studies.
Main Results:
- Intercellular adhesion molecule 5 (ICAM5), FUT8, and KLK13 identified as LUAD therapeutic candidates.
- ICAM5 demonstrated significant negative association with LUAD risk and emerged as an independent prognostic factor for patient survival.
- ICAM5 expression correlated with immune infiltration and showed no significant adverse phenotypes, supporting its safety.
Conclusions:
- ICAM5 is a promising biomarker with significant prognostic and therapeutic potential for lung adenocarcinoma.
- ICAM5 may modulate the tumor immune microenvironment and offers a potential therapeutic strategy for LUAD.
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