Order Matters: The Order of Somatic Mutations Influences Cancer Evolution.

Cancers evolve as a consequence of multiple somatic lesions, with competition between subclones and sequential subclonal evolution. Some driver mutations arise either early or late in the evolution of different individual tumors, suggesting that the final malignant properties of a subclone reflect the sum of mutations acquired rather than the order in which they arose. However, very little is known about the cellular consequences of altering the order in which mutations are acquired. Recent studies of human myeloproliferative neoplasms show that the order in which individual mutations are acquired has a dramatic impact on the cell biological and molecular properties of tumor-initiating cells. Differences in clinical presentation, complications, and response to targeted therapy were all observed and implicate mutation order as an important player in cancer biology. These observations represent the first demonstration that the order of mutation acquisition influences stem and progenitor cell behavior and clonal evolution in any cancer. Thus far, the impact of different mutation orders has only been studied in hematological malignancies, and analogous studies of solid cancers are now required.Work in the Kent laboratory is supported by a Bloodwise Bennett Fellowship (15008) and a European Hematology Association Non-Clinical Advanced Research Fellowship. Work in the Green laboratory is supported by Bloodwise, Cancer Research UK, the Kay Kendall Leukaemia Fund, the National Institute for Health Research Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer Medicine Centre, and the Leukemia and Lymphoma Society of America. D.G.K and A.R.G. are supported by a core support grant from the Wellcome Trust and MRC to the Wellcome Trust—Medical Research Council Cambridge Stem Cell Institut