Radiogenomics of Malignant Gliomas by Linking Physiological Mr Imaging, Histopathological Patterns, and Genetic Alternations: a Translational Study from Rat to Man

Glioblastoma is the most common malignant tumor of the central nervous system. Over 90% of diagnosed glioblastoma are primary cases, originating from glial cells and making up 80% of malignant brain tumors through multi-step oncogenesis. Despite the advances of treatment, the cure of malignant GBM remains elusive and the prognosis appears poor, partly due to under-sampling and mis-grading that influence the therapeutic strategy. Moreover, intra-tumoral and individual genetic heterogeneity remains another important issue. Therefore, an accurate grading of glioma by advanced imaging biomarkers that can address the heterogeneity of glioblastoma cannot be overemphasized. In addition to the heterogeneity at the histology level, primary glioblastoma are also characterized by heterogeneous alterations of gene expression, which consist of EGFR amplification, loss of PTEN, and loss of cyclin-dependent kinase inhibitors. The incorporation of oncogenomics to the imaging biomarkers, the radiogenomic, has recently emerged for cancer management. The key pathological features of glioblastoma, including cellularity, invasiveness, mitotic activity, angiogenesis, and necrosis can be evaluated with advanced MR imaging which can be used as glioma genomic signatures. By linking specific imaging biomarkers with specific gene expression profile could allow for more accurate diagnosis, prognosis prediction and better therapeutic guidance. In this three-year translational glioma project, we aim to investigate the advanced MR imaging biomarkers, the phonotypical expression, of gliomas with respect to their gene expression in preclinical animal model at 7T MRI and human subjects at 3T. To study intra-tumoral and inter-tumoral heterogeneity of glioblastomas, advanced MR imaging biomarkers such as perfusion-weighted imaging (PWI), CBF measurements by arterial spin labeling (ASL), high resolution diffusion tensor imaging (DTI), MR spectroscopy (MRS), Amide proton transfer (APT) image and Vessel size image will be used to depict the physiological as well as molecular events within the tumor. Genomic information will be acquired from microarray analysis. In addition to the frequently affected pathway including proliferation and angiogenesis, we will also focus on the DNA damage/repair genes, as radiation response of glioblastomas in Taiwanese is uniquely different from that Caucasian glioblastoma population. With the combined application of genomic information and multiparametric MRI, the tumor extent can be accurately defined, the therapeutic response can be better monitored and the prognosis can be well predicted. In summary, with the establishment of tumor radiogenomic platform, we will be able to unveil the genomic modification of glioblastoma from the perspective of molecular MRI through a bedside-to-bench translational research.