Abstract
Astrocytomas often recur after surgical resection, but the underlying mechanism remains enigmatic. Elucidation of clonal evolution in primary and relapse tumors may provide important information on tumor progression. Here, we examined genetic factors underlying recurrence in a patient with astrocytoma initially diagnosed with World Health Organization (WHO) grade II astrocytoma, who then relapsed with glioblastoma (WHO grade IV) complicated with local anaplastic astrocytoma (WHO grade III). We performed genomic DNA sequencing and data analysis of paired tumor tissue specimens and a peripheral blood sample (control), and used expands software for subclone analysis. A germline NOTCH1 missense mutation was identified in the peripheral blood sample, the primary tumor and the relapse tumor; in addition, we identified a tumor protein p53 (TP53) heterozygous nonsense mutation in the primary tumor and a TP53 homozygous nonsense mutation and an IDH1 heterozygous missense mutation in the relapse tumor. Clonal evolution trees indicated higher heterogeneity in the relapse tumor. Although germline mutations might contribute to the driving force of the primary tumor, aggressive chemotherapy and radiation may apply selective pressure for tumor clonal evolution; furthermore, a total loss of function of gatekeeping genes (TP53) may result in impaired DNA repair and catastrophic chromosomal aberrations.