Rare genetic event massively predisposes people to a form of leukemia
Researchers have found that people born with a rare abnormality of their chromosomes have a 2,700-fold increased risk of a rare childhood leukaemia. In this abnormality, two specific chromosomes are fused together but become prone to catastrophic shattering.
Acute lymphoblastic leukaemia, or ALL, is the most common childhood cancer. Scientists previously found that a small subset of ALL patients have repeated sections of chromosome 21 in the genomes of their leukaemia cells. This form of ALL – iAMP21 ALL – requires more intensive treatment than many other types of ALL. The scientists used modern DNA analysis methods to reconstruct the sequence of genetic events that lead to iAMP21 ALL.
The team noticed that some patients with iAMP21 ALL were born with an abnormality in which chromosome 15 and chromosome 21 are fused together. The researchers wanted to discover if this type of fusion (known as a Robertsonian translocation) was connected with this rare form of ALL. They found that the joining of the two chromosomes increases a person's risk of developing the rare iAMP21 form of ALL by 2,700 fold.
"Advances in treatment are improving patients' outcomes, but iAMP21 ALL patients require more intensive chemotherapy than other leukaemia patients," says Professor Christine Harrison, co-lead author from Newcastle University. "Although rare, people who carry this specific joining together of chromosomes 15 and 21 are specifically and massively predisposed to iAMP21 ALL."
"We have been able to map the roads the cells follow in their transition from a normal genome to a leukaemia genome."
The team developed new insights for analysing genome data that can reveal the sequence of complicated genetic changes that cause a healthy cell to become cancerous. They can now take a cancer cell at one point in time and deduce the relative timing and patterns of mutational events that occurred in that cell's life history.
The team sequenced nine samples from iAMP21 ALL patients, four with the rare Robertsonian translocation event and five that occurred in the general population. They found that for the four patients with the Robertsonian translocation, the cancer was initiated by a catastrophic genetic event known as chromothripsis. This event shatters a chromosome - in this case the joined chromosomes 15 and 21 - and then the DNA repair machinery pastes the chromosome back together in a highly flawed and inaccurate order. In the five other patients, the cancer was initiated by two copies of chromosome 21 being fused together, head to head, usually followed by chromothripsis.
"This is a remarkable cancer – for patients with iAMP 21 ALL we see the same part of the genome struck by massive chromosomal rearrangement," says Yilong Li, a first author from the Wellcome Trust Sanger Institute. "The method we've developed can now be used to investigate genetic changes in all cancer types."
The team found a consistent sequence of genetic events across the patients studied. Although the events at first sight seem random and chaotic, the end result is a new chromosome 21 in which the numbers and arrangement of genes are optimised to drive leukaemia.
The team will now use this method to decipher the genetic events that underlie many different cancer types.
"What is striking about our findings is that this type of leukaemia could develop incredibly quickly – potentially in just a few rounds of cell division," says Dr Peter Campbell, co-lead author from the Wellcome Trust Sanger Institute. "We now want to understand why the abnormally fused chromosomes are so susceptible to this catastrophic shattering."
Notes to Editors
Li Y, Schwab C, Ryan S, et al (2014) 'Constitutional and somatic genomic rearrangements coherently restructure chromosome 21 in acute lymphoblastic leukaemia'. Nature
Advanced online publication in Nature on 23 March, 2014.
This work was supported by the Wellcome Trust, Leukaemia and Lymphoma Research Specialist Programme, Research Foundation – Flanders (FWO) and the European Research Council.
A full list of participating centres appears on the Nature website.
Newcastle University is a Russell Group University. We rank in the top 20 UK universities in The Sunday Times 2013 University Guide. Amongst our peers Newcastle is: fifth in the UK for graduates into jobs (HESA 2011-12), 10th in the UK for student satisfaction and eighth in the UK for Medical research power and in the UK's top 12 for research power in Science and Engineering. 95 per cent of our students are in a job or further training within six months of graduating. We have a world-class reputation for research excellence and are spearheading three major societal challenges that have a significant impact on global society. These themes are: Ageing and Health, Sustainability, and Social Renewal. Newcastle University is the first UK university to establish a fully owned international branch campus for medicine at its NUMed Campus in Malaysia, which opened in 2011. Our International students put Newcastle University in world's top 12 (ISB 2011).
Leukaemia & Lymphoma Research is a leading UK charity dedicated to improving the lives of patients with all types of blood cancer, including leukaemia, lymphoma and myeloma. Its life-saving work is focused on finding causes, improving diagnosis and treatments, and running groundbreaking clinical trials for all blood cancer patients.
The charity champions patients' needs by influencing relevant policy and decision makers. Its communities give blood cancer patients and their families a place where they can find support and information and share their journey with other people who can relate to what they are going through. Around 30,000 people of all ages, from children to adults, are diagnosed with blood cancer every year in the UK.
The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.
Don Powell Media Manager
Wellcome Trust Sanger Institute
Hinxton, Cambridge, CB10 1SA, UK
Tel +44 (0)1223 496 928
Mobile +44 (0)7753 7753 97
Mary Clarke | EurekAlert!
Mobile phone test can reveal vision problems in time
11.02.2016 | University of Gothenburg
Proteomics and precision medicine
08.02.2016 | University of Iowa Health Care
Today, plants and microorganisms are heavily used for the production of medicinal products. The production of biopharmaceuticals in plants, also referred to as “Molecular Pharming”, represents a continuously growing field of plant biotechnology. Preferred host organisms include yeast and crop plants, such as maize and potato – plants with high demands. With the help of a special algal strain, the research team of Prof. Ralph Bock at the Max Planck Institute of Molecular Plant Physiology in Potsdam strives to develop a more efficient and resource-saving system for the production of medicines and vaccines. They tested its practicality by synthesizing a component of a potential AIDS vaccine.
The use of plants and microorganisms to produce pharmaceuticals is nothing new. In 1982, bacteria were genetically modified to produce human insulin, a drug...
Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock which attains an accuracy which had only been predicted theoretically so far. Their optical ytterbium clock achieved a relative systematic measurement uncertainty of 3 E-18. The results have been published in the current issue of the scientific journal "Physical Review Letters".
Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock...
The University of Würzburg has two new space projects in the pipeline which are concerned with the observation of planets and autonomous fault correction aboard satellites. The German Federal Ministry of Economic Affairs and Energy funds the projects with around 1.6 million euros.
Detecting tornadoes that sweep across Mars. Discovering meteors that fall to Earth. Investigating strange lightning that flashes from Earth's atmosphere into...
Physicists from Saarland University and the ESPCI in Paris have shown how liquids on solid surfaces can be made to slide over the surface a bit like a bobsleigh on ice. The key is to apply a coating at the boundary between the liquid and the surface that induces the liquid to slip. This results in an increase in the average flow velocity of the liquid and its throughput. This was demonstrated by studying the behaviour of droplets on surfaces with different coatings as they evolved into the equilibrium state. The results could prove useful in optimizing industrial processes, such as the extrusion of plastics.
The study has been published in the respected academic journal PNAS (Proceedings of the National Academy of Sciences of the United States of America).
Exceeding critical temperature limits in the Southern Ocean may cause the collapse of ice sheets and a sharp rise in sea levels
A future warming of the Southern Ocean caused by rising greenhouse gas concentrations in the atmosphere may severely disrupt the stability of the West...
12.02.2016 | Event News
09.02.2016 | Event News
02.02.2016 | Event News
12.02.2016 | Physics and Astronomy
12.02.2016 | Life Sciences
12.02.2016 | Medical Engineering