Mutation order influences cancer outcome

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.'