A unique study sequencing the entire genomes of identical twins with leukaemia has identified the first mutations sparking the disease in the mother’s womb.
The research, largely funded by Leukaemia & Lymphoma Research and conducted at The Institute of Cancer Research, London, has uncovered clues to the origins of childhood leukaemia in two pairs of identical twins.
Scientists believe these early genetic origins of childhood leukaemia could be ideal targets for new cancer drugs, because they represent mutations present in every single cancer cell, playing a major role in the development of the disease.
The study, which also received funding from the Kay Kendall Leukaemia Fund and Cancer Research UK,was published in the major scientific journal PNAS.
Leukaemia is the most common cancer diagnosed in children, affecting a third of young cancer sufferers and killing 100 children a year in the UK. Identical twin children often develop leukaemia at the same time, suggesting a genetic link for their disease.
The Institute of Cancer Research scientists decided to investigate this link by sequencing the entire three billion letter genome of two pairs of identical twins with leukaemia, in order to identify the mutations driving the disease in the womb and after birth.
Co-author of the study, Professor Mel Greaves, Professor of Cell Biology at The Institute of Cancer Research (ICR), said: “It’s unusual in cancer to be able to identify the mutation that kick starts the whole process. Twin children, uniquely, provide an insight into the silent beginnings of leukaemia. One implication of these new findings is that the first or ‘founder’ mutation might provide an appropriate target for therapy as, unlike all subsequent mutations, it is present in every cancer cell.”
The ICR scientists took genetic samples from two sets of identical twins suffering from acute lymphoblastic leukaemia (ALL), the most common form of leukaemia found in children. They found that a common leukaemia causing gene called ETV6-RUNX1, generated in the womb by the exchange of genetic material between chromosomes, was the only significant mutation shared by two of the twins and therefore must have been the critical ‘initiating’ genetic change leading to their leukaemia.
The two identical twins exhibited a total of 22 mutations which had accumulated after birth, but none of these mutations were shared by both twins, and so were secondary to the disease’s progression.
In the second pair of identical twins, both children were found to have inherited a mutation from their parents called NF1, predisposing them to a condition called neurofibromatosis, which is a major risk factor for leukaemia. Three other chromosome changes were identified in both twins, which the scientists believe occurred in utero from the same single clone of cells.
Co-author, Professor Richard Houlston, Professor of Molecular and Population Genetics at the ICR, said: “From a clinical perspective, it’s very rare that you will get a set of identical twins with lymphoblastic leukaemia, so to be able to sequence the whole genome of two pairs of twins with this disease is an important achievement. This study helps us to better understand how leukaemia develops in utero, and provides us with promising new avenues for treatment.”
Professor Chris Bunce, Research Director at Leukaemia & Lymphoma Research, said; “The research team at the ICR has been at the forefront of studies into leukaemia in twins that have developed a deeper understanding of the types and sequence of events that lead to blood cells becoming cancerous. This study has used state of the art emerging technologies to still further understand how cancer develops. Although the study was performed in young twins, it reveals processes that are relevant to adult leukaemias, which are far more common, and also potentially relevant to other cancers.”