NOVEL BIOMARKERS OF MALIGNANT PROGRESSION IN RECURRENT LOW GRADE GLIOMA

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The goal of the proposed study is to evaluate the role of noninvasive imaging parameters as biomarkers of malignant transformation in diffuse low grade glioma and to use these parameters to select regions for characterizing the genetic mutations associated with recurrent disease. The studies will have a significant impact on the management of these patients by providing objective criteria to predict when a lesion transforms to a more malignant phenotype, whether and where to intervene surgically and how to select the next line therapy. This is an important problem because patients with tumors that recur from a prior LGG have different outcomes depending on histological subtype, grade, and molecular/cytogenetic features. The mechanisms of malignant transformation are unclear and treatment strategies are often pursued without histological confirmation of recurrent tumor. In our previous SPORE Project, we applied magnetic resonance imaging (MRi) and spectroscopic imaging (MRS!) to evaluate 125 patients prior to resection of tumors that were thought to have recurred from a prior LGG. Significant differences in the in vivo MR measures were seen for tumors with malignant transformation compared to those that did not. Ex vivo analysis of the histological status, IDHI mutations and ex-vivo NMR spectra from the image guided tissue samples provided new information that resulted in novel hypotheses being investigated in Specific Aim 1. Extending this approach by defining the mutation profile using next-generation sequencing of image guided tissue samples with defined histology will increase the probability of identifying mutations that drive malignant transformation and address, for the first time, the tumor genome evolution associated with treatment effects and the natural history of the disease.Specific Aim 1 will relate in-vivo MR parameters to malignant transfomriation and clinical outcome and Specific Aim 2 will use paired samples from lesions that either do or do not have the characteristics of malignant transformation, as well as paired samples from the current and subsequent surgery to examine the evolution of the mutation profile. The knowledge gained will make a major impact upon patient care. RELEVANCE (See instructions); This novel project will integrate non-invasive imaging markers that predict malignant transformation with an evaluation of the spatial and temporal patterns of changes in genetic mutations of patients who present with recurrent disease from an original diagnosis of low grade glioma. This will inform on the mechanisms of malignant transformation and will facilitate the development of strategies to prevent or treat the recurrence.