3270 - Effect of Pelvic Radiation on Systemic Gene Expression Changes in a Prospective Study of Non-Metastatic Prostate Cancer
Presenter(s)
B. George1, C. Jin1, P. Auer2, M. Xiaolong1, B. Marples3, J. H. Oh4, W. A. Hall5, and S. L. Kerns5; 1Medical College of Wisconsin, Milwaukee, WI, 2Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, 3Department of Radiation Oncology, University of Rochester, Rochester, NY, 4Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, 5Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI
Purpose/Objective(s): Prostate cancer is a common pelvic malignancy for which radiation therapy (RT) is often used as a curative treatment. RT can lead to local tissue injury in the genitourinary and gastrointestinal tracts as well as systemic effects such as fatigue, which may be driven more by function changes than RT-mediated cell killing. The effects of pelvic RT on systemic gene expression and the role variable gene expression plays on these patient outcomes have not yet been described. We hypothesize that pelvic RT alters the whole-blood transcriptome of men treated for prostate cancer, reflecting systemic molecular and cellular changes.
Materials/Methods: RNA sequencing was performed using whole blood from 192 patients with non-metastatic prostate cancer who were enrolled on a prospective observational study of genetic biomarkers of RT late effects (K07CA187546). Samples were collected at baseline (pre-RT) and at end of treatment (post-RT) from patients treated with conventional or moderate hypofractionation. To isolate gene expression changes from changes in blood composition, cell type deconvolution was performed via CIBERSORT and confirmed against lab measured cell counts (N=30 with labs <30 days before RT). Transcript-wise changes were analyzed using linear mixed-effects models adjusted for cell-population shifts (fixed effect) and batch/participant (random effects). Pathway enrichment was characterized using GSEA (MSigDB ‘C5’).
Results: RT induced significant systemic alterations in blood cell composition and gene expression. Principle component analysis (PCA) based on all transcripts showed robust separation between pre- and post-RT samples (PC1 paired t-test, p < 1×10-13). Post-RT, there was a mean decrease in the proportion of T cells and increase in the proportion of neutrophils and monocytes (all p < 1×10-15). After adjusting for changes in blood cell composition, 9,892 transcripts were significantly differentially expressed (Benjamini Hochberg False discovery rate < 0.05) from pre-RT to post-RT. Of note, these included upregulation of PHLDA3 and MiR-34a, which both act downstream of the p53 pathway and were previously identified as radiosensitive genes in preclinical models. Top enriched pathways included porphyrin and H2O2 metabolism pathways.
Conclusion: This is the first large-cohort study to characterize global transcriptomic shifts in whole blood following pelvic RT. Many genes and pathways, within and beyond DNA repair, remained significantly RT-responsive after accounting for cell-population changes. These findings offer insight into biological mechanisms of radiotoxicity and may inform future predictive models for adverse clinical outcomes.