MTR-16MISMATCH REPAIR DEFECTS PREDICT CLINICAL OUTCOME OF PRIMARY AND RECURRENT MALIGNANT GLIOMAS

Abstract

INTRODUCTION: Temozolomide (TMZ), a standard drug for glioblastoma (GBM), induces inactivation of the DNA mismatch repair (MMR) system and hence causes hypermutator phenotype in the glioma especially with methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter. MMR defects are also found in primary gliomas and are associated with resistance to TMZ and malignant progression to secondary GBM. However, the association between alteration of MMR system and clinical outcome of both primary and recurrent GBMs was yet to be elucidated. METHODS: We analyzed protein expression of MLH1, MSH2, MSH6, and PMS2 as well as MGMT methylation in a set of 117 primary GBMs and 34 paired sample of initial and recurrent gliomas. Protein expression was analyzed by Western blotting and/or immunohistochemistry. MGMT methylation was determined by methylation-specific PCR. Progression-free and overall survival times according to each molecular status were reviewed. RESULTS: Loss of MMR protein expression (MLH1, MSH2, MSH6, and PMS2) was observed in 12%, 10%, 50%, and 16% of the primary samples, respectively. Inactivation of MSH6 during the recurrence was associated with MGMT methylation at recurrence (p = 0.02), while MGMT methylation of the initial samples did not predict the changes of any MMR protein. Malignant progression from lower grade glioma was associated with inactivation of MSH6 (p = 0.035). Loss of MMR protein expression, as well as unmethylated MGMT promoter, was associated with shorter overall survival in patients with primary GBMs. In contrast, MMR inactivation was associated with longer survival in patients with recurrent GBMs, while MGMT methylation was not. CONCLUSION: Inactivation of MMR protein was associated with resistance to TMZ for primary GBMs, malignant progression of lower grade gliomas, and was predictive factor for survival of the patients with recurrent GBMs. Further investigation to define optimal treatment for glioma according to MGMT and MMR status is warranted.