Integrative analysis of XPC and VEGFA as risk biomarkers in T-cell lymphoma: A case-control study

Introduction: T-cell lymphoma (TCL) is a rare and aggressive type of non-Hodgkin lymphoma (NHL) that accounts for around 12% of all cases and shows variable clinical and molecular features. Germline single-nucleotide polymorphisms (SNPs) have been increasingly recognized as modulators of cancer risk. However, the role of such genetic variants in TCL in a non-western population remains largely unexplored. Therefore, we aimed to investigate the relationship between XPC, VEGFA and TNFAIP8 SNPs and the risk of developing TCL in an Arab population. Methods: A total of 31 TCL patients and 289 matched healthy controls were recruited from King Abdullah University Hospital (KAUH), Females represented 32.3% (n=10) of patients and 61.3% (n=146) of controls, with mean ages of 44.1 and 43.2 years, respectively. Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue samples for lymphoma cases and from peripheral blood samples for controls. Selected SNPs were genotyped using a sequencing protocol, and significant ones were identified using adjusted p-values and the Bonferroni false discovery rate (FDR) correction. We validated our findings using the GEO cohort (GSE6338) and performed linear modeling of microarray data to identify differentially expressed genes, applying a cutoff of log2FC > 0.5. All analyses were conducted in R version 4.4.3. Results: The primary cohort showed that XPC rs2228001G>T was associated with higher TCL risk in both the co-dominant [TT: OR 2.353; 95% CI 1.01-5.59; p=0.0471] and recessive models [TT: OR 2.811; 95% CI 1.29-6.08; p=0.0084]. VEGFA rs3025039C>T also showed a strong association with increased risk in the co-dominant [TT: OR 19.091; 95% CI 4.70-78.99; p=0.00003], dominant [OR 3.227; 95% CI 1.36-7.75; p=0.0076], and recessive [OR 15.333; 95% CI 3.94-60.06; p=0.00006] models. Conversely, TNFAIP8 rs1045241C>T showed a protective effect in the co-dominant [OR 0.158; 95% CI 0.02-0.56; p=0.0141], dominant [OR 0.382; 95% CI 0.14-0.92; p=0.0446], and over dominant models [OR 0.152; 95% CI 0.02-0.53; p=0.0116]. In the validation dataset (GSE6338), VEGFA showed significant upregulation (LogFC=0.598; adj. p=0.000795), while XPC showed no significant change (LogFC=0.090; adj. p=0.457). Conclusion: This study identifies VEGFA rs3025039 as a potential genetic risk factor for T-cell lymphoma in the Jordanian population. Gene expression analysis further confirmed upregulation of VEGFA in TCL validation cohort, suggesting a possible role in disease progression. These findings provide the first evidence in an Arab population cohort linking specific SNPs and gene expression changes to TCL risk, offering potential targets for population-specific personalized therapies.