An Integrated Approach Combining Mathematical And Genomic Methods To Reveal The Optimal Timing Of Therapeutic Intervention In Who Grade Ii Diffuse Glioma

Abstract BACKGROUND In WHO grade II diffuse gliomas (low-grade gliomas, hereafter called LGGs), chemotherapy and radiotherapy contribute to prolonged survival but could induce somatic mutations. The optimal timing of treatment in LGGs remain poorly understood. To delineate this, we designed a mathematical model for tumor growth and investigate the association among the treatment, malignant transformation (MT), and the accumulation of somatic mutations revealed by whole exome sequencing (WES) in LGGs. METHODS Totally, 290 patients with LGGs between 1990 and 2018 were analyzed. We assessed the statuses of IDH mutation and 1p19q co-deletion in all tumors. Among all, 114 patients (39%) underwent MT during follow-up periods (mean: 82.6 months). Tumor volume was evaluated with FLAIR and/or T2-weighted MRI. MT was evaluated with contrast-enhanced MRI and/or pathological diagnosis. To investigate the number of somatic mutations in a cohort of LGGs and their patient matched recurrence, WES was performed on 88 serial samples collected at least two time-points from 39 patients. RESULTS Oligodendroglioma, IDH-mutant and 1p/19q-codeleted (OD) showed longer transformation-free survival compared to other subtypes. An exponential model was chosen to estimate growth rate in LGGs, since the exponential model provided a better fit to our data as compared to a linear model. The growth rate significantly decreased in the middle of chemotherapy and after radiotherapy. By contrast, these treatments increased the number of somatic mutations identified by WES and the rate of MT in each subtype. The increasing number of mutations in recurrent tumors showed strong correlation with the rise in MT rate. Based on the growth rate and the risk of MT, optimal timing of treatments could be calculated for each genetic subtype. CONCLUSIONS The mathematical model and WES analysis delineates the optimal timing of treatments in each subtype, which will help to decide the treatment for LGGs.