Abstract
Previously, transcriptomic profiling studies have shown distinct molecular subtypes of glioblastomas. It has also been suggested that the recurrence of glioblastomas could be achieved by transcriptomic reprograming of tumors, however, their characteristics are not yet fully understood. Here, to gain the mechanistic insights on the molecular phenotypes of recurrent glioblastomas, gene expression profiling was performed on the 43 cases of glioblastomas including 15 paired primary and recurrent cases. Unsupervised clustering analyses revealed two subtypes of G1 and G2, which were characterized by proliferation and neuron-like gene expression traits, respectively. While the primary tumors were classified as G1 subtype, the recurrent glioblastomas showed two distinct expression types. Compared to paired primary tumors, the recurrent tumors in G1 subtype did not show expression alteration. By contrast, the recurrent tumors in G2 subtype showed expression changes from proliferation type to neuron-like one. We also observed the expression of stemness-related genes in G1 recurrent tumors and the altered expression of DNA-repair genes (i.e., AURK, HOX, MGMT, and MSH6) in the G2 recurrent tumors, which might be responsible for the acquisition of drug resistance mechanism during tumor recurrence in a subtype-specific manner. We suggest that recurrent glioblastomas may choose two different strategies for transcriptomic reprograming to escape the chemotherapeutic treatment during tumor recurrence. Our results might be helpful to determine personalized therapeutic strategy against heterogeneous glioma recurrence.
Highlights
Glioblastoma is the most aggressive and frequent primary brain tumor with dismal prognosis [1, 2]
By performing integrative gene expression profile analyses, we have demonstrated that there are two distinct subtypes of transcriptomic reprograming during recurrence of glioblastomas
Further interrogation has revealed the differential expression of MGMT and MSH6 between the subtypes (Fig 4B), which suggested the involvement of distinct mechanisms for TMZ resistance during recurrence of glioblastomas
Summary
Glioblastoma is the most aggressive and frequent primary brain tumor with dismal prognosis [1, 2]. New diagnostic and therapeutic strategies for tumor recurrence might be required to improve clinical outcomes of patients. There is a conflicting observation that the molecular subtypes are not altered by recurrence [11], remaining the mechanisms for tumor recurrence still unveiled. With this concern, in the present study, we re-evaluated the alteration of the molecular phenotypes of recurrent glioblastomas by comparing gene expression profiles of paired primary and recurrent glioblastomas. We could identify two different modes of transcriptomic reprograming during recurrence of glioblastomas, and which implied subtype-specific mechanisms for the acquisition of drug-resistance by tumor recurrence. Our analysis may provide new mechanistic and clinical insights on the recurrent glioblastoma management
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