PI3K/AKT and SHH singling pathway contribute to metastasis relapsed during gene evolution in human Oligodendroglioma

Abstract Background: Oligodendroglioma shows a relatively better prognosis, responds well to radiotherapy and chemotherapy, and rarely progress to a very aggressive tumor. Little is known about the evolution of genetic and epigenetic changes that occur in the progression of oligodendroglioma. Methods: We evaluated gene evolution changes in progressive relapsed oligodendroglioma based on deep whole-genome-sequencing data(ctDNA). We analyzed longitudinal genomic and molecular data from 6 patients under therapy. Multiple metastasis recurrence occurred in 5 cases.Results: Whole-exome sequencing demonstrated that the rate of shared mutation between the primary tumors and recurrent tumors or TISF was relatively low. In two cases, even well-known presumptive major driver mutations of CIC and FUBP1 that were detected in primary tumors were not detected at relapsed TISF. Among them, 2 cases converted into IDH1 wild state in the process of gene evolution under stress treatment, indicating that the cell phenotype and genetic characteristics of oligodendroglioma will change in the process of tumor evolution, and metastasis relapsed is a later event. Two patients underwent long-term chemotherapy before operation, we find that recurrence tumors harbor mutations in PI3K/AKT and sonic hedgehog(SHH) singling pathways. One case showed hypermutation when it recurred, with a clear mutational signature, lead to the rapid progress of the tumor. Conclusions: Oligodendroglioma has great spatial and temporal heterogeneity during gene evolution, lead to the rapid progress of the tumor. Metastasis relapsed is a later event during oligodendroglioma progression. PI3K/AKT and SHH signaling pathway plays an important role in promoting tumor metastasis and drug resistance during the relapsed of oligodendrocytes. Cell phenotype and genetic characteristics of oligodendroglioma will also change in the process of tumor evolution, tendency to increase the malignant degree of the tumor. Trial registration: The report was retrospectively registered in Zhengzhou University People’s Hospital, and the registration number is 2122432055 and date of registration should be in March, 2021.