Deciphering Non-Viral Oncogenesis Mechanisms in Solid Organ Transplant Recipients: A Multi-Omic Integrative Analysis

Solid organ transplant recipients (SOTRs) face a substantially elevated risk of malignancy, with cancer representing a leading cause of long-term morbidity and mortality in this population. While viral-associated post-transplant malignancies have been extensively characterized, the molecular mechanisms underlying non-viral oncogenesis in immunosuppressed individuals remain poorly understood despite their significant contribution to excess cancer burden. This doctoral dissertation employed a multi-omic integrative analysis framework to elucidate the molecular pathways driving non-viral tumor initiation and progression in SOTRs. Leveraging data from The Cancer Genome Atlas (TCGA), Scientific Registry of Transplant Recipients (SRTR), NCI Transplant Cancer Match (TCM) Study, and Gene Expression Omnibus (GEO) repositories, this research characterized genomic, transcriptomic, and immunological features across 1,847 tumor samples, including 312 tumors from confirmed transplant recipients. Genomic analysis revealed that SOTR tumors exhibited significantly lower tumor mutational burden compared to immunocompetent controls (median 3.2 vs. 4.8 mutations/Mb, p < .001), with distinct mutational signatures including elevated APOBEC-associated and mismatch repair deficiency signatures. Transcriptomic profiling demonstrated profound immune microenvironment alterations, characterized by significantly reduced CD8+ T-cell infiltration, decreased activated dendritic cells, and elevated M2 macrophage polarization. Integrative clustering identified four distinct molecular subtypes with differential survival outcomes: Immune-Depleted/High-Proliferative, Genomically-Unstable, Metabolically-Altered, and Immune-Moderate. Machine learning classification achieved excellent discrimination (AUC = 0.89) for distinguishing SOTR tumors, while the risk prediction model demonstrated strong performance (AUC = 0.82) for cancer risk stratification. Overall survival was significantly worse for SOTR cancer patients (5-year OS: 42.3% vs. 58.7%; HR = 1.67, p < .001). These findings provide novel empirical evidence supporting the cancer immunoediting hypothesis in human post-transplant malignancies and identify actionable molecular targets and biomarkers for personalized surveillance and therapeutic intervention in the growing population of immunosuppressed individuals. Keywords: solid organ transplantation, non-viral oncogenesis, immunosuppression, multi-omic analysis, cancer immunoediting, tumor microenvironment, post-transplant malignancy