The expression of mismatch repair proteins MLH1, MSH2 and MSH6 correlates with the Ki67 proliferation index and survival in patients with recurrent glioblastoma.
OBJECTIVE
There is a growing body of evidence that deficiency of DNA mismatch repair proteins other than O(6)-methylguanine-DNA methyltransferase (MGMT) also contributes to glioblastoma recurrence. We examined the protein expression of MLH1, MSH2 and MSH6 in paired  initial and recurrent glioblastoma and compared the results to the Ki67 proliferation index and patient survival.


METHODS
Forty-two patients were included who met the following inclusion criteria: (1) histologically confirmed primary glioblastoma; (2) total tumour resection at initial  craniotomy; (3) re-craniotomy for recurrence. Immunohistochemical staining was performed using specific monoclonal antibodies against MLH1, MSH2, MSH6 and Ki67. Chi-square test, Wilcoxon test and log-rank test (Cox-Mantel) were used for statistical analysis.


RESULTS
In recurrent  tumours, MLH1 expression was significantly reduced. MLH1, MSH2 and MSH6 expression in initial lesions was significantly associated with the Ki67 proliferation index. MLH1 and MSH2 expression in recurrent lesions was also significantly associated with the Ki67 proliferation index. MLH1 and  MSH6 positivities in initial lesions were indicators of reduced patient survival.


CONCLUSIONS
Our results indicate a potential important role of MLH1 and MSH6 in glioblastoma progression. Specific attention should be given on the role of MLH1 and MSH6 in patients with glioblastoma  recurrence during temozolomide treatment.
Stark
Andreas M
AM
Department of Neurosurgery, Schleswig-Holstein University Medical Center, Campus Kiel, Germany. starka@nch.uni-kiel.de
Doukas
Alexander
A
Hugo
Heinz-Hermann
HH
Mehdorn
H Maximilian
HM
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D053843:DNA Mismatch Repair / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000096:biosynthesis* / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D015996:Survival Rate / Q000639:trends
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D019394:Ki-67 Antigen; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein