Order matters: sequence of genetic mutations determines how cancer behaves

The order in which genetic mutations are acquired determines how an individual cancer behaves, according to research from the University of Cambridge, published today in the New England Journal of Medicine.

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 as cells divide. In a study published today, researchers at the Department of Haematology, 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 characterised by the over-production of mature blood cells together with an increased risk of both blood clots and leukaemia. 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 behaviour of single blood stem cells.

Using samples collected primarily from patients attending Addenbrooke’s Hospital, part of the Cambridge University Hospitals, researchers showed that patients who acquire mutations in JAK2 prior to those in TET2 display aberrant blood counts over a decade earlier, are more likely to develop a more severe red blood cell disease subtype, are more likely to suffer a blood clot, and their cells respond differently to drugs that inhibit JAK2. 

Professor Tony Green, who led the study, adds: “This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy. These results show how study of the MPNs provides unparalleled access to the earliest stages of tumour development (inaccessible in other cancers, which usually cannot be detected until many mutations have accumulated). This should give us powerful insights into the origins of cancer.”

Work in the Green Lab is supported in part by Leukaemia and Lymphoma Research and Cancer Research UK. Additional funding came from the Kay Kendall Leukaemia Fund; the NIHR Cambridge Biomedical Research Centre; the Cambridge Experimental Cancer Medicine Centre; the Leukemia & Lymphoma Society of America; the Canadian Institutes of Health Research; and the Lady Tata Memorial Trust. 

Read more: http://www.cam.ac.uk/research/news/order-matters-sequence-of-genetic-mutations-determines-how-cancer-behaves


Ortmann, CA and Kent, DG et al. The Impact of Mutation Order on Myeloproliferative Neoplasms. NEJM; 11 Feb 2015.

Order matters

The Influence of Mutation Order on the Fate of Myeloproliferative Syndromes.

Image credit:

Charles Swanton, M.D., Ph.D.

N Engl J Med 2015; 372:661-663February 12, 2015DOI: 10.1056/NEJMe1414288

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