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Mutation order influences cancer outcome

16 February 2015
Appeared in BioNews 790

The order in which mutations occur in a cell can determine the clinical outcome of certain cancers, according to research published in the New England Journal of Medicine.

The researchers isolated and examined individual, healthy and cancerous stem cells from the blood of patients with myeloproliferative neoplasms (MPNs) - a group of pre-leukemic disorders.

By identical or 'clonal' expansion of each of the isolated cells, the researchers were able to study the evolution of mutations seen in these conditions, which often concern two genes called JAK2 and TET2.

They reported that patients in whom the JAK2 gene was mutated before the TET2 gene were more likely to have a worse disease course, suffering blood clots and other symptoms, over a decade earlier than those who had a mutation in the TET2 gene first. However, the JAK2-first affected patients were more responsive to available anti-JAK2 drugs.

Dr David Kent, one of the study authors, from the University of Cambridge, said: 'This surprising finding could help us offer more accurate prognoses to MPN patients based on their mutation order and tailor potential therapies towards them. For example, our results predict that targeted JAK2 therapy would be more effective in patients with one mutation order but not the other.'

MPNs are characterised by a functionally impaired bone marrow, the tissue responsible for blood production. The result is over-accumulation of blood cells which increase the risk of blood clots and leukaemia. MPNs are often early identified through routine blood tests and are generally treatable, as they represent an earliest stage of cancer. The researchers, however, suggest that the findings may apply to solid tumours too.

Professor Antony Green, who led the study, noted: '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.'

Effect of Mutation Order on Myeloproliferative Neoplasms
New England Journal of Medicine |  12 February 2015
Mutation Order in Tumor Genes Affects Cancer Outcome
Scientific American |  11 February 2015
Order matters: sequence of genetic mutations determines how cancer behaves
University of Cambridge (press release) |  11 February 2015
Order of genetic faults may dictate how cancers behave
Cancer Research UK |  11 February 2015
Order of Mutation Acquisition Predicts Clinical Progression in MPNs
Medscape |  11 February 2015
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