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Uncovering cancer’s roots

Posted on 28 March, 2014 by Graham Shaw

Studying cancer evolution can help us discover the earliest mutations that cause tumours to form, improving future treatments and reducing the risk of relapse.

For patients diagnosed with aggressive cases of leukaemia, it can seem to come like a bolt out of the blue. Acute myeloid leukaemia (AML) is a fairly rare type of cancer, with only 2,500 patients diagnosed in the UK each year; some patients diagnosed with AML may only have months to live and whilst 40% might live longer than five years, overall long-term survival is poor.

A review by Dr Nicola Potter and Professor Mel Greaves, from The Institute of Cancer Research in London, highlights some exciting developments in our understanding of how AML develops, and what the earliest mutations in the process might be.

Professor Greaves is an expert in the biology of leukaemias, but he is also a pioneer in applying the principles of evolutionary biology to answer some fundamental questions of cancer research - what determines the protracted and unpredictable development of cancer, and why are we seeing drug resistance so frequently?

The ICR recently announced the opening of the Centre for Evolution and Cancer, to investigate the evolutionary biology of cancer and its application in the clinic. The centre is the first of its kind and scale in the world, allowing scientists to come together to explore exciting new avenues of cancer-related evolutionary research.

The ICR review highlights a new study in Nature led by award-winning Canadian scientist Dr John Dick, the first person to identify cancer stem cells in leukaemia. His team found that a mutation often found in cancer cells of patients with AML, called DNMT3A, was also found in healthy T-cells from their immune system.

This was surprising as T cells are not involved in the cancer and, despite having the DNMT3 mutation in common with the cancer cells, they lacked other alterations important to the development of AML. They deduced that the mutation must arise in ancestral cells that go on to form T cells and AML, suggesting the DMNT3 mutation is an important early change that contributes to the disease well before cancer develops.

The researchers tested their hypothesis and found that haematopoietic stem cells (HSCs) - precursor cells from which many types of blood cell develop - are the first cells to harbour the DNMT3A mutation. This indicates that AML starts with a DNMT3A mutation in HSCs generating a pre-malignant population of cells, with later genetic changes in descendent cells leading to patients developing AML.

The study helps us to understand how AML evolves, but it could also have important implications for detecting and treating the disease.

The researchers also found the DNMT3A mutation in the HSCs of patients who had undergone chemotherapy, indicating that some of these pre-leukaemic cells had evaded treatment. The presence of these cells after therapy suggests that even the most potent treatments available may not be completely effective, leading to patient relapse months or years down the line.

But despite this stark message, the study raises exciting opportunities for the future.

There are currently no targeted therapies routinely used in the treatment of AML, but this new research suggests that DNMT3A is one of the earliest mutations driving the formation of the disease, so drugs that target this mutation could lead to more effective treatments.

Assessing DNMT3A could also be a useful way for doctors to check if the disease has returned after treatment. At the moment patients aren’t routinely screened for DNMT3A, but as a founding mutation for AML, its presence would be a strong indicator of relapse. The Nature study highlights how cancer can evolve from seemingly benign mutations. At the ICR, our new Centre for Evolution and Cancer will be examining whether insights like this could hold the key to fighting the disease in the future.


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