11C-MET-PET/CT guided multi-target biopsy and transcriptome analysis demonstrated the cellular functional heterogeneity in DIPG

Objective To explore the cellular heterogeneity between 11C-methionine (11C-MET) high and low regions in the diffuse intrinsic pontine glioma (DIPG) using 11C-MET-PET/CT guided multiple-target biopsy and transcriptome analysis. Methods Six DIPG patients admitted to Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University from January 2017 to December 2017 were included in this prospective study. The 11C-MET-PET/CT image was imported into GE AW4.5 workstation software to measure the maximum methionine uptake value (SUVmax) of the tumor, and the tumor area was divided into methionine high uptake zone, middle uptake zone and low uptake zone. Biopsy was performed on the high and low intake areas of methionine. By sequencing the tissue samples, the differentially expressed genes and hotspot mutations in the high and low methionine regions of 6 patients were compared, and gene ontology (GO) analysis and signal pathway enrichment analysis were performed. Results The number of genes up-regulated in the methionine-high uptake area of tumor tissues in 6 patients was 296-1 768, and the expression was down-regulated from 558 to 1 476. The results of detection of common hotspot mutations in methionine high and low uptake areas of 6 patients were as follows: 1 BCOR mutation, 4 H3F3A mutations, 1 PIK3CA mutation, 5 TP53 mutations, and 1 PPM1D mutation (detected only in the 11C-MET low uptake region). GO and signal pathway enrichent analysis showed that compared with the low methionine uptake area of tumor tissue, the genes highly expressed in the high uptake area were mainly involved in tumor proliferation, invasion and neovascularization, while the low expressed genes were mainly involved in immune cell chemotaxis, immune response and biological processes such as the reaction to interferon. Conclusions The heterogeneity of cell function is exhibited in the tissues of DIPG. Compared with the lower uptake region of methionine, high uptake region has high expression of tumor malignant biological behavior-related genes and low expression of immunosuppressive and tumor resistance-related genes. 11C-MET-PET/CT could have diagnostic value in distinguishing the biological functions of tumor cells. Key words: Brain stem neoplasms; Genetic testing; Positron-emission tomography; 11C-methionine; Heterogeneity