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Acute Myeloid Leukaemia is 11 diseases
Acute Myeloid Leukaemia is 11 diseases
- Analysis of 111 leukaemia-causing genes from 1540 AML patients reveals repeating ‘constellations’ of genetic changes driving the disease;
- Genetic complexity helps explain why survival rates vary so dramatically;
- Findings will provide more accurate prognoses for patients with different types of AML, help researchers identify optimal drug combinations and design better clinical trials.
Hinxton, UK, 8 June 2016 – An international study led by scientists at the Wellcome Trust Sanger Institute has shown that Acute Myeloid Leukaemia (AML) is not one, but at least 11 different diseases. Published in the New England Journal of Medicine, the research shows that different ‘constellations’ of genetic changes can explain why survival rates vary among AML patients. The findings can improve the way patients are diagnosed and treated, help researchers develop optimal treatment strategies and design better clinical trials for testing novel drugs.
Acute myeloid leukaemia (AML) is an aggressive blood cancer that affects people of all ages, often requiring months of intensive chemotherapy in hospital. It develops in cells in the bone marrow.
In the largest study of its kind, researchers analysed more than 100 genes known to cause leukaemia in 1540 patients with AML. The large amounts of high quality genetic and clinical of for each patient helped the team identify common genetic themes that drive the development of the disease. The analysis revealed that patients fell into at least 11 major groups, each of which featured specific combinations of genetic changes and distinctive clinical features.
Most patients had a unique constellation of genetic changes driving their leukaemia, which helps explain why survival rates vary so much among AML patients.
“Leukaemia is a global problem with poor outcomes for most patients,” said Dr Elli Papaemmanuil, joint first author from the Sanger Institute and the Memorial Sloan Kettering Cancer Centre in New York. “We combined detailed genetic analysis with patient health information to help understand the fundamental causes of AML. For the first time, we untangled the genetic complexity seen in most AML cancer genomes into distinct evolutionary paths that lead to AML. By understanding these paths we can help develop more appropriate treatments for individual patients with AML. We are now extending such studies across other leukaemias.”
Gathering enough data to see patterns in genetic changes is a huge challenge, as cohorts tend to be relatively small and results recorded in very different ways. That means it can be hard to tell what factors cause different constellations of genetic changes. In this study, the clinical data contributed by the German-Austrian AML Study Group represented standardised treatments as well as complete, consistent information.
“It was known for some time that AML is caused by many different genetic changes, but now we begin to see a structure behind the complexity – one that is correlated with differences in outcome – and that translates directly to how a person responds to clinical treatment,” explains Moritz Gerstung, who conducted the analysis at the Sanger Institute and now leads a research group at EMBL-EBI. “Thanks to the sheer numbers we were working with, and the right statistical tools, we could clearly see the evidence for different categories – and that is something we couldn’t have seen before, as most of these mutations occur in only a small fraction of patients.”
Full knowledge of the genetic make-up of a patient’s leukaemia substantially improved the ability to predict whether that patient would be cured with current treatments. This information could be used to design new clinical trials to develop the best treatments for each AML subtype, with the ultimate aim of bringing more extensive genetic testing into routine clinical practice.
“Having a well-described dataset representing over 1000 patients made a huge difference,” says Moritz. “It confirmed the categories we already knew about, and revealed several more that had not been described before. This mean that we can now put a label on many patients which so far did not fall into a clear disease category, and give more precise prognosis. Now that we know what those characteristic genetic changes are behind each type, we can tackle them.”
Dr Peter Campbell, co-leader of the study from the Wellcome Trust Sanger Institute, said: “Two people may have what looks like the same leukaemia down the microscope, but we find extensive differences between those leukaemias at the genetic level. What is exciting is that these genetic differences can explain so much of why one of those patients will be cured, while the other will not, despite the exact same treatment.”
Prof. Hartmut Döhner, Medical Director of Hematology/Oncology at Ulm University and chair of the German-Austrian AML Study Group, said: “These results represent a major step forward in translating the exciting findings from molecular genetics into better disease classification, diagnosis, and improved care of our patients with acute myeloid leukaemia.”
The team is exploring tools for determining prognosis for myeloid leukaemia, and eventually other cancers, to better inform patient decision making.
The work was supported by the Wellcome Trust, Bundesministerium fur Bildung und Forschung, Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft, the European Hematology Association, Amgen and the Kay Kendall Leukaemia Fund.
Dr Samantha Wynne, Press Office, Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, United Kingdom. Tel. 01223 492 368, E-mail firstname.lastname@example.org