Explaining and exploiting the spectrum of isocitrate dehydrogenase driver mutations in different tumour types (360G-Wellcome-210804_Z_18_Z)

Recently, there has been great interest in mutational processes in cancer. This project looks at the other side of the coin, namely important genetic changes in cancer that cannot be explained by mutational processes and hence probably result from natural selection. The driver oncogenes IDH1 and IDH2 are frequently mutated in several cancer types, including some with a very poor prognosis. The mutations cause de novo production of the "oncometabolite" D2HG. Pathogenic IDH1 and IDH2 mutations occur at specific amino acids, but the mutation spectrum varies strikingly across cancer types, independent of underlying mutational processes. Preliminary evidence suggests that different IDH mutations vary in their ability to produce D2HG and the most frequent mutations may not make the most D2HG. This project tests the model that tissues vary quantitatively in their D2HG production and/or detoxification and/or activation of oncogenic pathways in response to D2HG. We hypothesise that the most common IDH mutations in each tumour type are selected to produce the level of D2HG that best promotes tumorigenesis. We shall test whether some mutations actually produce too much D2HG for efficient tumour growth, opening up exciting new therapeutic opportunities based not on targeting mutant IDH, but on raising D2HG levels.