Order of Acquired Gene Mutations Can Have Huge Impact on Cancer Progression; Pioneering Research Offers Powerful New Insights into Origins of Cancer

The order in which genetic mutations are acquired determines how an individual cancer behaves, according to research from the University of Cambridge, published today, February 11, 2015, in the New England Journal of Medicine. The article was entitled, “The Impact of Mutation Order on Myeloproliferative Neoplasms.” Most of the genetic mutations that cause cancer result from environmental “damage” (for example, through smoking or as a result of over-exposure to sunlight) or from spontaneous errors occurring as cells divide. In a study published today, researchers in the Department of Hematology, the Cambridge Institute for Medical Research and the Wellcome Trust/Medical Research Council Stem Cell Institute show, for the first time, that the order in which such mutations occur can have an impact on disease severity and response to therapy. The researchers examined genetically distinct single stem cells taken from patients with myeloproliferative neoplasms (MPNs), a group of bone marrow disorders that are characterized by the over-production of mature blood cells, together with an increased risk of both blood clots and leukemia. These disorders are identified at a much earlier stage than most cancers because the increased number of blood cells is readily detectable in blood counts taken during routine clinical check-ups for completely different problems. Approximately one in ten of MPN patients carry mutations in both the JAK2 gene and the TET2 gene. By studying these individuals, the research team was able to determine which mutation came first and to study the effect of mutation order on the behavior of single blood stem cells.
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