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Integrative multi-omics and Mendelian randomization identify WWOX and THBS2 as potential therapeutic targets in
Yinjie Qin1, Jiayue Wei1, Yingzhi He1
1Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China.
Background:
Mature T/NK-cell lymphoma is a highly heterogeneous, aggressive non-Hodgkin lymphoma. Due to the lack of specific therapeutic targets, treatment outcomes for patients with relapsed/refractory (R/R) disease are limited, and survival rates are low. Therefore, there is an urgent need to explore specific therapeutic targets and treatment strategies based on molecular mechanisms.
Methods:
Multi-omics data including genome-wide association study (GWAS), cis-expression quantitative trait loci (cis-eQTL), and cis-protein quantitative trait loci (cis-pQTL) were integrated through Mendelian Randomization (MR) and Bayesian colocalization analyses to identify and validate potential therapeutic targets. Summary-data-based MR (SMR) analysis strengthened causal inference, while cis-methylation quantitative trait loci (cis-mQTL) data integration elucidated genetic regulatory mechanisms. Transcriptome analysis assessed target biological functions, and phenome-wide MR evaluated the risk-benefit profile of target interventions. Drug prediction and molecular docking assessed therapeutic potential of these targets.
Results:
WWOX was identified as a protective factor and THBS2 as a risk factor, both with strong colocalization support. SMR analysis revealed close associations between WWOX expression, DNA methylation, and disease risk. Transcriptome analysis indicated that WWOX and THBS2 participate in tumor proliferation, invasion, and immune regulation. Phenome-wide MR analysis suggested that tissue-specific targeting is crucial for THBS2 inhibition. Drug prediction preliminarily validated the therapeutic potential of epigenetic regulatory drugs.
Conclusions:
This study identifies WWOX and THBS2 as potential therapeutic targets for mature T/NK-cell lymphoma. Treatment strategies based on epigenetic reprogramming and immune microenvironment regulation targeting WWOX and THBS2 provide new directions for precision therapy of this refractory lymphoma.
Insights
This study identifies WWOX and THBS2 as key targets for mature T/NK-cell lymphoma, offering new precision therapy directions. Epigenetic reprogramming and immune microenvironment modulation show promise for treating this aggressive cancer.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Mature T/NK-cell lymphoma is an aggressive non-Hodgkin lymphoma with poor outcomes in relapsed/refractory cases.
- Limited specific therapeutic targets necessitate novel treatment strategies.
- Understanding molecular mechanisms is crucial for developing effective therapies.
Purpose of the Study:
- To identify and validate novel therapeutic targets for mature T/NK-cell lymphoma using multi-omics data integration.
- To explore the genetic regulatory mechanisms and biological functions of potential targets.
- To assess the therapeutic potential and risk-benefit profile of targeting identified factors.
Main Methods:
- Integrated genome-wide association study (GWAS), cis-eQTL, cis-pQTL, and cis-mQTL data using Mendelian Randomization (MR) and Bayesian colocalization.
- Employed Summary-data-based MR (SMR) for causal inference and transcriptome analysis for functional assessment.
- Utilized phenome-wide MR for risk-benefit evaluation and drug prediction/molecular docking for therapeutic potential assessment.
Main Results:
- WWOX identified as a protective factor and THBS2 as a risk factor for mature T/NK-cell lymphoma with strong colocalization.
- SMR analysis indicated associations between WWOX expression, DNA methylation, and disease risk.
- Transcriptome analysis revealed WWOX and THBS2 roles in tumor proliferation, invasion, and immune regulation; phenome-wide MR highlighted tissue-specific targeting for THBS2 inhibition.
- Drug prediction suggested potential for epigenetic regulatory drugs.
Conclusions:
- WWOX and THBS2 are identified as promising therapeutic targets for mature T/NK-cell lymphoma.
- Epigenetic reprogramming and immune microenvironment regulation targeting WWOX and THBS2 offer new avenues for precision therapy.
- This research provides a foundation for developing targeted treatments for refractory mature T/NK-cell lymphoma.
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