Peripheral Blood Transcriptomic Profile Associated with Cutaneous Radiation Injury in Cancer Patients Undergoing Radiotherapy

The peripheral blood transcriptomic profile associated with clinically observed cutaneous radiation injury (CRI) during fractionated radiotherapy remains incompletely characterized. We analyzed blood transcriptomes from 22 adults receiving radiotherapy: 10 with CRI and 12 without radiation-related skin injury at blood collection. RNA was assayed using two-color Agilent microarrays. Variance filtering retained 12,251 probes that were evaluated using four complementary analyses: preranked Gene-Set Enrichment Analysis (GSEA) for ranked gene-set enrichment, Gene-Set Variation Analysis (GSVA) for sample-level gene-set scoring, weighted gene co-expression network analysis for co-expression structure, and differential expression analysis at the probe level. GSEA identified positive enrichment of interferon-γ response and E2F targets and negative enrichment of heme metabolism. Consistently, GSVA showed higher interferon-response, E2F-target, unfolded-protein-response, and cholesterol-homeostasis scores and lower angiogenesis, xenobiotic-metabolism, protein-secretion, hypoxia, and heme-metabolism scores in participants with CRI. Ten modular co-expression networks met the data-derived CRI-correlation prioritization criterion. Positively correlated networks were enriched for negative regulation of response to wounding and complement/coagulation cascades. Intramodular connectivity and sample-level expression analyses prioritized KDM4C and PARPBP as exploratory high-connectivity candidates, with both retaining top-10 connectivity in 95.5% of leave-one-out iterations. Exploratory differential expression analysis identified 1842 probes, comprising 585 upregulated and 1257 downregulated probes in CRI. Genes mapped from downregulated probes were significantly enriched for ribosome, spliceosome, and oxidative phosphorylation pathways. Across complementary analytical frameworks, CRI was associated with a coherent peripheral blood profile characterized by interferon and cell-cycle enrichment; altered wound-response and complement/coagulation processes; reduced heme-metabolism, angiogenesis, and xenobiotic-metabolism scores; and downregulated transcripts involved in ribosomal function, RNA processing, and mitochondrial energy metabolism. Although the cross-sectional design and later sampling of CRI participants precluded full separation of CRI-associated differences from treatment-time and cumulative-exposure effects, these findings extend the molecular characterization of CRI and identify pathways and high-connectivity candidates for longitudinal assessment of reproducibility, temporal dynamics, and potential diagnostic or predictive relevance.