11 Feb Order of Mutations Affects Disease Pattern in Chronic Blood Disorders
Medical Research: What is the background for this study? What are the main findings?
Dr. Kent: Cancers are the result of the sequential acquisition of errors in the genetic code. Most studies have focused on the sum of these mutations (e.g., A+B+C = cancer) but no study in patients has asked the question of whether or not the order of genetic mutations impacts the disease (e.g., does A to AB equal B to BA). We studied patients with chronic blood disorders (known as myeloproliferative neoplasms, or MPNs) that are precursors to cancer to access the earliest stages of tumour development and studied whether or not the order of mutation acquisition impacted disease. We studied patients with mutations in two genes (JAK2 and TET2) and showed that the order of acquisition of these mutations impacted timing of clinical presentation, disease subtype, frequency of thrombotic events, and differed in their response to targeted therapy in the lab.
Medical Research: What should clinicians and patients take away from your report?
Dr. Kent: Two main findings for clinicians to take away are firstly that the order of mutation acquisition can impact disease pathogenesis and patients with known mutations may have distinct diseases depending on which mutation came first and secondly for those treating myeloproliferative neoplasms, patients that a JAK2-first disease is significantly different to a TET2-first disease and the order of acquisition has clinical implications for timing of presentation and thrombotic risk.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Kent: The order of acquisition of mutations should be studied in other cancers to determine if similar clinical stratification could be applied. Order of mutation should be considered in clinical trial design as well.
Secondly we need to understand the molecular mechanism by which a first mutation can change the cell such that the second mutation does not have the same effect that it would normally have if it came first.
Christina A. Ortmann, M.D., David G. Kent, Ph.D., Jyoti Nangalia, M.B.Chir., F.R.C.Path., Yvonne Silber, M.Sc., David C. Wedge, Ph.D., Jacob Grinfeld, M.B., Ch.B., F.R.C.Path., E. Joanna Baxter, Ph.D., Charles E. Massie, Ph.D., Elli Papaemmanuil, Ph.D., Suraj Menon, Ph.D., Anna L. Godfrey, F.R.C.Path., Ph.D., Danai Dimitropoulou, B.Sc., Paola Guglielmelli, M.D., Ph.D., Beatriz Bellosillo, Ph.D., Carles Besses, M.D., Ph.D., Konstanze Döhner, M.D., Claire N. Harrison, D.M., F.R.C.Path., George S. Vassiliou, F.R.C.Path., Ph.D., Alessandro Vannucchi, M.D., Peter J. Campbell, M.B., Ch.B., Ph.D., and Anthony R. Green, F.R.C.Path., F.Med.Sci.
MedicalResearch.com Interview with: David G. Kent, Ph.D (2015). Order of Mutations Affects Disease Pattern in Chronic Blood Disorders MedicalResearch.com;