Immunohistochemical analysis of ATRX, p53 and IDH Gene mutations in glioblastoma patients and their co-relations with patient survival in Seoul National University Hospital, Seoul, South Korea

Abstract

Glioblastoma (GBM) is the most common malignancy of central nervous system and is classified according to morphologic criteria established by the World Health Organization (WHO) into grade IV astrocytoma. With the most advanced treatments they have a very poor patient prognosis with average overall survival in the range of about 12 months. Recently molecular studies revealed that some molecular variants are associated with better survival outcomes as compared to others and may be used as prognostic markers. Mutations of ATRX, p53 and IDH genes are frequently reported to be present as well as associated with survival outcome in GBM. Material and method- We evaluated the mutation status of ATRX, p53 and IDH genes immunohistochemically in 156 unselected GBM patients and analyzed their association with overall patient survival in order to find out if they can be considered for distinguishing clinically distinct prognostic subgroups of GBM. We compared the immunohistochemical characteristics of ATRX, p53 and IDH genes in adult and pediatric GBM. We evaluated the survival outcome of GBM cases based on different treatment modalities used. Results- We found that 62.2% unselected GBM tumors showed loss of ATRX expression, 72.4% tumors had overexpression of p53 protein and 10.2% tumors were mutant for IDH1. We found that loss of ATRX expression and IDH1 mutations are associated with better patient survival while the p53 wild type is associated with a better patient survival as compared to overexpression of p53 protein. Patients with loss of ATRX expression had median overall survival of 20.2 months as compared to 13.5 months for patients who showed ATRX expression

similarly patients having IDH1 mutant GBM had a better median overall survival of 28.6 months as compared to 15.5 months for GBM patients with wild type IDH1. However, patients showing mutant expression of p53 had a poor overall survival of 15.5 months as compared to 21.6 months for patients who had negative expression of p53. We also found that there were statistically significant survival differences when these genes were analyzes in different two and three gene combinations. While carrying out immunohistochemical and survival outcome analysis in pediatric and adult GBM cases separately we found that immunohistochemically pediatric GBM are different from adult GBM in genetic signature expressions. Survival analysis of adult GBM cases showed similar results as of unselected GBM survival outcome results.. Conclusion- Aberrant expressions of ATRX, p53, and IDH encoded by different tumor regulatory genes frequently occur in GBM and also, that mutant ATRX, mutant IDH and negative expression of p53 protein individually and their combinations are associated with statistically better patient outcome, which may be used as prognostic factors in GBM.