| Summary: | Since the initial discovery of recurrent isocitrate dehydrogenase 1 (<i>IDH1)</i> mutations at Arg132 in glioma, <i>IDH1</i> 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 <i>IDH1</i> 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 <i>IDH1</i> 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 <i>TP53</i> (tumor protein p53) co-occur significantly with <i>IDH1</i> mutations and show a tendency of exclusivity to <i>IDH2</i> mutations. The co-occurrence of <i>IDH1</i> mutation and <i>TP53</i> alteration is widespread in glioma, particularly in those harboring <i>IDH1<sup>R132H</sup></i>, <i>IDH1<sup>R132G</sup></i>, and <i>IDH1<sup>R132S</sup></i>, whereas co-occurrence of <i>IDH1<sup>R132C</sup></i> and <i>TP53</i> alteration can be found sporadically in other cancer types. In keeping with the importance of p53 in tumor suppression, <i>TP53</i> 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 <i>IDH1</i> hotspot mutation and <i>TP53</i> alteration and the importance of <i>TP53</i> status as a predictor of patient outcome in lower-grade glioma.
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