Abstract
Since the initial discovery of recurrent isocitrate dehydrogenase 1 (IDH1) mutations at Arg132 in glioma, IDH1 hotspot mutations have been identified in cholangiocarcinoma, chondrosarcoma, leukemia, and various other types of cancer of sporadic incidence. Studies in glioma and leukemia have helped promote the theory that IDH1 mutations are an oncogenic event that drives tumorigenesis in general. Through bioinformatic analysis of more than 45,000 human pan-cancer samples from three independent datasets, we show here that IDH1 mutations are rare events in human cancer but are exclusively prevalent in WHO grade II and grade III (lower-grade) glioma. Interestingly, alterations in the tumor-suppressor gene TP53 (tumor protein p53) co-occur significantly with IDH1 mutations and show a tendency of exclusivity to IDH2 mutations. The co-occurrence of IDH1 mutation and TP53 alteration is widespread in glioma, particularly in those harboring IDH1(R132H), IDH1(R132G), and IDH1(R132S), whereas co-occurrence of IDH1(R132C) and TP53 alteration can be found sporadically in other cancer types. In keeping with the importance of p53 in tumor suppression, TP53 status is an independent predictor of overall survival irrespective of histological and molecular subgroups in lower-grade glioma. Together, these results indicate tissue specificity of IDH1 hotspot mutation and TP53 alteration and the importance of TP53 status as a predictor of patient outcome in lower-grade glioma.