Abstract

Cancers result from the accumulation of somatic mutations and their properties are thought to reflect the sum of these mutations. However, virtually nothing is known about whether or not the order in which these mutations are accrued has an impact on disease pathogenesis.  Numerous important studies have discussed "mutational order" as the stepwise accumulation of key mutations during tumorigenesis, with some mutations driving genetic instability (e.g., p53) and others priming specific subsequent mutations (e.g., genetic canalisation). We have recently demonstrated in human malignancies that the evolution of a tumour is also influenced by the order in which its mutations are acquired. Specifically, clinical presentation, risk of thrombosis, and clonal evolution are distinct in patients with myeloproliferative neoplasms who acquire JAK2V617F mutations prior to TET2 mutations compared to those that acquire TET2 mutations before JAK2V617F. We have now used clonal stem and progenitor cell assays to show that the impact of a given mutation is dependent on whether it is acquired in a wild-type or a single mutant cell, meaning that the consequences of each mutation are shaped by the effects of the preceding mutation. This new model is not only biologically compelling but also of significant clinical importance as knowledge of mutation order could predict stage of disease or treatment response based on the evolution of the stem cell compartment.