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.<\/p>\n\n\n\n
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.<\/p>\n\n\n\n
\u201cAll patients who had inherited a mutation in the TP53<\/em> gene showed signs of chromothripsis in their tumour cells, but none of the patients with normal TP53<\/em> did\u201d says Jan Korbel, who led the genomics research at EMBL, \u201cso this mutation must be involved either in shattering chromosomes, or in preventing the cell from reacting when a chromosome shatters.\u201d<\/p>\n\n\n\n This strong link between the hereditary TP53<\/em> mutation and chromothripsis has implications for diagnosis and treatment.<\/p>\n\n\n\n \u201cAs clinicians, if we find evidence of chromothripsis in a medulloblastoma sample, we can now look for an inherited mutation in the TP53<\/em> gene\u201d says Stefan Pfister, who led the work at the DKFZ, \u201cand we know that any family members who also have the mutation should be screened regularly, as they\u2019ll have a very high risk of developing particular types of cancer, including brain tumours.\u201d<\/p>\n\n\n\n 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 \u2013 the protein encoded by TP53<\/em> \u2013 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<\/em> 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.<\/p>\n\n\n\n