Whole Blood Transcriptional Fingerprints of High-Grade Glioma and Longitudinal Tumor Evolution under Carbon Ion Radiotherapy

SIMPLE SUMMARY: Particle therapy with carbon ions is a promising novel option for the treatment of recurrent high-grade glioma (rHGG). Lack of initial and sequential biopsies limits the investigation of rHGG evolution under therapy. We hypothesized that peripheral blood transcriptome derived from liquid biopsies (lbx) as a minimal invasive method may provide a useful decision support for identification of glioma grade and provide novel means for longitudinal molecular monitoring of tumor evolution under carbon ion irradiation (CIR). We demonstrate feasibility and report patient, tumor and treatment fingerprints in whole blood transcriptomes of rHGG patients with pre-CIR and three post-CIR time points. ABSTRACT: Purpose: To assess the value of whole blood transcriptome data from liquid biopsy (lbx) in recurrent high-grade glioma (rHGG) patients for longitudinal molecular monitoring of tumor evolution under carbon ion irradiation (CIR). Methods: Whole blood transcriptome (WBT) analysis (Illumina HumanHT-12 Expression BeadChips) was performed in 14 patients with rHGG pre re-irradiation (reRT) with CIR and 3, 6 and 9 weeks post-CIR (reRT grade III:5, 36%, IV:9, 64%). Patients were irradiated with 30, 33, 36 GyRBE (n = 5, 6, 3) in 3GyRBE per fraction. Results: WTB analysis showed stable correlation with treatment characteristics and patients tumor grade, indicating a preserved tumor origin specific as well as dynamic transcriptional fingerprints of peripheral blood cells. Initial histopathologic tumor grade was indirectly associated with TMEM173 (STING), DNA-repair (ATM, POLD4) and hypoxia related genes. DNA-repair, chromatin remodeling (LIG1, SMARCD1) and immune response (FLT3LG) pathways were affected post-CIR. Longitudinal WTB fingerprints identified two distinct trajectories of rHGG evolution, characterized by differential and prognostic CRISPLD2 expression pre-CIR. Conclusions: Lbx based WTB analysis holds the potential for molecular stratification of rHGG patients and therapy monitoring. We demonstrate the feasibility of the peripheral blood transcriptome as a sentinel organ for identification of patient, tumor characteristics and CIR specific fingerprints in rHGG.