Impact of Clonal Hematopoiesis on Gene Expression in the Solid Tumour Microenvironment
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Authors
Buttigieg, Marco Michael
Date
2024-07-03
Type
thesis
Language
eng
Keyword
Clonal hematopoiesis , Immunology , Aging , Genetics , Transcriptomics , Tumour Microenvironment , Cancer
Alternative Title
Abstract
Background: Clonal hematopoiesis (CH) is caused by somatic mutations that provide a fitness advantage in hematopoietic stem cells, contributing to inflammation and disease. CH is common in patients with solid tumours and has shown context-dependent associations with survival; however, its contribution to the tumour microenvironment (TME) remains unclear.
Methodology: We tested 8,927 patients across 32 cancers in The Cancer Genome Atlas cohort. CH calls were derived from peripheral blood and tumour whole exome sequencing (WES) data, and CH was defined as the presence of a somatic driver mutation at variant allele frequency (VAF) ≥2% in blood. Overall survival analysis was conducted using Cox proportional hazard models, controlled for age, sex, tumour type, and metastatic status. Tumour bulk RNA-sequencing data was processed for differential gene expression and gene set enrichment analysis. Abundance of immune cell populations was estimated with CIBERSORTx.
Results: 1,045 CH mutations were identified in 780 patients (8.74%). CH mutations were mostly found in the epigenetic regulators DNMT3A and TET2. 129 peripheral blood CH mutations were also detected in tumour WES (CH-Tum). CH and CH-Tum were associated with worse overall survival, but only in univariate modelling. CH-Tum was associated with increased inflammation and immune infiltration in the TME across cancers. In specific tumour types, we observed associations between CH and CH-Tum with elevated inflammation.
Conclusion: CH is common, even prior to therapy, in patients with solid tumours and may be linked with poor outcomes. CH in the TME dysregulates the anti-tumor immune response in a tumour-specific manner. Further study is needed for mechanistic discovery and biomarker development to realize the potential of CH in immuno-oncology and improve patient outcomes.
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Attribution-NonCommercial-NoDerivatives 4.0 International
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NonCommercial-NoDerivatives 4.0 International