Order matters: sequence of genetic mutations determines how cancer behaves

cjb250 — Wed, 11 Feb 2015 22:00:00 +0000

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.

̽��ֱ��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 ̽��ֱ�� 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.

Dr David Kent, one of the study’s lead authors, says: “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.”

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.

Dr Matt Kaiser, Head of Research at Leukaemia & Lymphoma Research, said: “We are becoming more and more aware that a cancer’s genetic signature can vary from patient to patient, and we are becoming better at personalising treatment to match this. ̽��ֱ��discovery that the order in which genetic errors occur can have such a big impact on cancer progression adds an important extra layer of complexity that will help tailor treatment for patients with MPNs. ̽��ֱ��technology to do this sort of study has been available only recently and it shows once again how pioneering research into blood cancers can reveal fundamental insights into cancer in general.”

Dr Áine McCarthy, Science Information Officer at Cancer Research UK, says: “ ̽��ֱ��methods used in this pioneering research could help improve our understanding of how cancer cells develop mutations and when they do so. This interesting study suggests that the order in which genetic faults appear can affect how patients respond to different drugs – this insight could help doctors personalise treatment to make it more effective for each patient.”

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

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.

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

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

Tony Green

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Red blood cells (illustration)

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Unraveling tumour growth one stem cell at a time

gm349 — Tue, 04 Jun 2013 16:06:35 +0000

Researchers at the ̽��ֱ�� of Cambridge have discovered that a single mutation in a leukaemia-associated gene reduces the ability of blood stem cells to make more blood stem cells, but leaves their progeny daughter cells unaffected. Their findings have relevance to all cancers that are suspected to have a stem cell origin as they advance our understanding of how single stem cells are subverted to cause tumours.

Published this week in PLOS Biology, the study by Professor Tony Green and his team at the Cambridge Institute for Medical Research (CIMR) is the first to isolate highly purified single stem cells and study their individual responses to a mutation that can predispose individuals to a human malignancy. This mutation is in a gene called JAK2, which is present in most patients with myeloproliferative neoplasms (MPNs)—a group of bone marrow diseases that are characterized by the over-production of mature blood cells and by an increased risk of developing leukaemia.

Using a unique mathematical modelling approach, carried out in collaboration with Professor Ben Simons at the Cavendish Laboratory in Cambridge, in combination with experiments on single mouse stem cells, the researchers identified a distinct cellular mechanism that operates in stem cells but not in their daughter cells.

“This study is an excellent example of an inter-disciplinary collaboration pushing the field forward,” says lead author Dr David Kent. “Combining mathematical modelling with a large number of single stem cell assays allowed us to predict which cells lose their ability to expand. We were able to reinforce this prediction by testing the daughter cells of single stem cell divisions separately and showing that mutant stem cells more often undergo symmetric division to give rise to two non-stem cells.”

Characterizing the mechanisms that link JAK2 mutations with this pattern of stem cell division—a pattern that eventually leads to the development of MPNs—will inform our understanding of the earliest stages of tumour establishment and of the competition between tumour stem cells, say the authors. ̽��ֱ��next step, currently underway at the Cambridge Institute for Medical Research, is to understand the effect that acquiring additional mutations has on blood stem cells, as these are thought to drive the expansion of blood progenitor cells, leading to the eventual transformation to leukaemia that occurs in patients with MPNs.

Citation: Kent DG, Li J, Tanna H, Fink J, Kirschner K, et al. (2013) Self-Renewal of Single Mouse Hematopoietic Stem Cells Is Reduced by JAK2V617F Without
Compromising Progenitor Cell Expansion. PLoS Biol 11(6): e1001576. doi:10.1371/journal.pbio.1001576

Press release provided by PLOS Biology.

Study has relevance to all cancers that are suspected to have a stem cell origin

David Kent, Tony Green Lab

A small colony of cells derived from a single blood stem cell. Hundreds of such colonies were assessed for their proliferation kinetics and blood cell types produced.

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̽��ֱ�� of Cambridge - David Kent

Order matters: sequence of genetic mutations determines how cancer behaves

Unraveling tumour growth one stem cell at a time