Rise of oligodendroglioma hypermutator phenotype from a subclone harboring TP53 mutation after TMZ treatment

Abstract

Oligodendrogliomas characterized and defined by 1p/19q co-deletion are slowly growing tumors showing better prognosis than astrocytomas. TP53 mutation is rare in oligodendrogliomas while the vast majority of astrocytomas harbor the mutation, making TP53 mutation mutually exclusive with 1p/19q codeletion in lower grade gliomas virtually. We report a case of 51-year-old woman with a left fronto-temporal oligodendroglioma that contained a small portion with a TP53 mutation, R248Q, at the initial surgery. On a first, slow-growing recurrence 29 months after radiation and nitrosourea-based chemotherapy, the patient underwent TMZ chemotherapy. The recurrent tumor responded well to TMZ but developed a rapid progression after 6 cycles as a malignant hypermutator tumor with a MSH6 mutation. Most of the recurrent tumor lacked typical oligodendroglioma morphology that was observed in the primary tumor, while it retained the IDH1 mutation and 1p/19q co-deletion. The identical TP53 mutation observed in the small portion of the primary tumor was universal in the recurrence. This case embodied the theoretically understandable clonal expansion of the TP53 mutation with additional mismatch repair gene dysfunction leading to hypermutator phenotype. It thus indicated that TP53 mutation in oligodendroglioma, although not common, may play a critical role in the development of hypermutator after TMZ treatment.