An inherited mutation in a gene known as the guardian of the genome is likely the link between exploding chromosomes and some particularly aggressive types of cancer, scientists at the European Molecular Biology Laboratory (EMBL), the German Cancer Research Centre (DKFZ) and the University Hospital, all in Heidelberg, Germany, have discovered.
Their study, published online today in Cell, also presents the first whole genome sequence of a paediatric tumour: medulloblastoma, a brain cancer which is the second most common cause of childhood mortality in developed countries, where only car accidents cause more deaths in children.
Looking at the complete genome sequence of these tumours, the scientists found one or two chromosomes in each cell had countless parts in the wrong order, were missing some genes, and had extra copies of others. Such extensive rearrangements suggested that those chromosomes had been shattered, like a bead necklace that is pulled too hard, and then wrongly reassembled. But the scientists only found these telltale signs of chromosome explosion, or chromothripsis, in samples from a specific group of patients.
“All patients who had inherited a mutation in the TP53 gene showed signs of chromothripsis in their tumour cells, but none of the patients with normal TP53 did” says Jan Korbel, who led the genomics research at EMBL, “so this mutation must be involved either in shattering chromosomes, or in preventing the cell from reacting when a chromosome shatters.”
This strong link between the hereditary TP53 mutation and chromothripsis has implications for diagnosis and treatment.
“As clinicians, if we find evidence of chromothripsis in a medulloblastoma sample, we can now look for an inherited mutation in the TP53 gene” says Stefan Pfister, who led the work at the DKFZ, “and we know that any family members who also have the mutation should be screened regularly, as they’ll have a very high risk of developing particular types of cancer, including brain tumours.”
Cancer treatments often involve killing the tumour cells by damaging their DNA with chemo- or radiotherapy, but these treatments also affect healthy cells in the surrounding tissue. If those cells have healthy copies of p53 – the protein encoded by TP53 – this gene will monitor the genome, and if it finds too much damage it will instruct the cells to stop dividing, sending them into the cellular equivalent of old age (senescence) or suicide (apoptosis). But if a patient has inherited the TP53 mutation from their parents, all their cells will have faulty copies of this gene, including the cells surrounding the tumour. Thus, those healthy cells will have trouble dealing with the DNA damage caused by such treatments, and could become cancerous themselves. So the findings have immediate clinical implications in that such patients should not be given DNA-damaging chemotherapy or high-dose radiotherapy, since both would greatly increase the likelihood of secondary cancers.
The scientists believe that the TP53 mutation may also play a role in causing chromosomes to shatter in the first place, by shortening telomeres, the caps that keep chromosome ends from fraying. This could make arms from different chromosomes more likely to get stuck to each other and shatter if they’re pulled in different directions. Since telomeres naturally shorten with age, this could explain why, when the German scientists expanded their study to another cancer – an aggressive form of leukaemia in adults – they found that patients who had both a non-inherited TP53 mutation and evidence of chromothripsis were typically of an advanced age.
“Chromothripsis is thought to cause two to three percent of all human cancers,” says Korbel, “so if we can really prove how the TP53 mutation affects this process, it could have a big impact on our understanding of how healthy cells in the body turn into tumours.”
The study was undertaken as part of the International Cancer Genome Consortium (ICGC), an effort to study 50 different types of cancer worldwide.
“This study shows the power of combining genome sequencing and clinical expertise,” says Peter Lichter from DKFZ, and member of the ICGC scientific steering committee: “cancer genome sequencing can help to understand why patients can react so differently to cancer treatments, and may also lead to the development of new anti-cancer drugs.”Policy regarding use
Sonia Furtado Neves | EMBL Research News
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences