gms | German Medical Science

Objective: There is evidence that defective DNA mismatch repair (MMR) results in tolerance to temozolomide regardless of O(6)-alkylguanine-DNA alkyltransferase (AGT) activity. Dysfunction of MMR genes, in particular MLH1, MSH2, and MSH6, leads to loss of MMR protein expression and to microsatellite instability (MSI). We examined the MLH1, MSH2, and MSH6 expression status in paired initial and recurrent GBM.

Methods: The protein expression of MLH1, MSH2 and MSH6 in paired probes of initial and recurrent glioblastoma (GB) was examined by immunohistochemistry. Samples of 36 patients were included who underwent craniotomy for glioblastoma between 1999 and 2006. Significant changes in protein expression were defined as under- or overexpression of at least 20%.

Results: The mean age of the patients was 65.4 years (range: 39–89 years). The male:female ratio was 1.4:1. All patients received post-operative radiotherapy, 3 patients received combined chemo‑/radiotherapy after the initial operation. 17 patients received temozolomide after recurrence. The mean expression values were: MLH1 in initial GB=69%, MLH1 in recurrent GB=58%; MSH2 initial=75%, MSH2 recurrent=69%, MSH6 initial=21%, MSH6 recurrent=20%. We saw downregulation of MLH1 in 14 (39%) and up-regulation in 5 (14%) cases. Downregulation of MSH2 was noted in 7 (19%) cases, and up-regulation also in 7 (19%) cases. MSH6-downregulation was observed in 3 (8%) and up-regulation also in 3 (8%) cases. Downregulation of MSH2 was more frequent in patients who received temozolomide later on. In contrast, downregulation of MLH1 and MSH6 was not associated with administration of chemotherapy. Protein expression changes were not associated with patient survival.

Conclusions: Downregulation of MLH1 protein expression is frequent in glioblastoma. In contrast, the expression of MSH2 is more stable in initial versus recurrent lesions. The expression of MSH6 was comparable in initial and recurrent tumors.