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

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.

The impact of tumor metabolic activity assessed by 18F-FET amino acid PET imaging in particle radiotherapy of high-grade glioma patients

“…Finally, using WBT profiling of a subset of the rHGG cohort, we found gene expression differences associated with SUVmax, adjusted for initial tumor grade (stable initial grade WBT signature as recently reported ( 23 )). Among them were genes involved in DNA repair (ATM and POLD4).…”

“…Different blood components have the potential to yield information about the tumor with minimal intervention, i.e., circulating tumor cells, or other fractions of blood cells, which might be exposed to a number of transcriptome-altering factors (e.g., irradiation, drug treatments, and transversion through tumor tissue and modulation by cytokines). We recently reported the feasibility of WBT lbx to monitor response to treatment (particle irradiation in rHGG) and to mirror tumor characteristics ( 23 ). We therefore aim to evaluate if tracer uptake is linked to a specific whole-blood transcriptome fingerprint.…”

UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells

“…POLD4 has been observed in the development and progression of multiple cancers, including hepatocellular carcinoma [ 15 ], lung cancer[ 16 , 17 ], and cisplatin resistance in gastric cancer [ 18 ]. In GBMs, POLD4 is associated with cancer patient resistance to radiotherapy and tumor recurrence [ 19 ]. Nevertheless, the underlying specific mechanisms that enable POLD4 to promote GBM radiotherapy resistance remain unclear.…”

Recurrent Glioblastoma: What Is the Route?

“…Carbon ion irradiation (CIR) may be a novel therapeutic option for recurrent high-grade gliomas. Knoll et al performed a whole blood transcriptome analysis via liquid biopsy for monitoring the longitudinal molecular changes that occur under this type of therapy [ 18 ]. Another irradiation option, photodynamic therapy (PDT) using talaporfin sodium (NPe6) (NPe6-PDT), was recently approved in clinical practice.…”