publicado em 09/04/2013 às 10h55:00
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Discovered indicators of onset of childhood leukemia in the womb

New research made with identical twins may reveal new targets for therapies and ideal anticancer drugs

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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, is published today (Monday) 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 shared genetic or environmental factors.

Scientists at The Institute of Cancer Research (ICR) decided to investigate this link by sequencing the entire 3 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.

Study co-author Professor Mel Greaves, Professor of Cell Biology at The Institute of Cancer Research, 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."

Researchers 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 mutation arises in one cell in one twin, with cells carrying the mutation then spreading to the other twin via their shared circulation in the womb.

The two identical twins exhibited a total of 22 other mutations, but none of these mutations were shared by both twins, and so they must have accumulated after birth as the disease progressed.

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 Institute of Cancer Research, 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."

Dr Julie Sharp, senior science information manager at Cancer Research UK, said: " This interesting research shows how studying the DNA of twins can shed light on the genetic mistakes that first initiate cancer in children and the subsequent faults that occur as the cancer evolves. Studies like this could reveal new ways to target the very roots of cancer and help us better understand how the disease develops over time. Survival rates have increased significantly over the past decades thanks to research, but there is still more to do to make treatments better with fewer side effects."

   Palavras-chave:   Leukemia    Genetic mutations    Uterus    Institute of Cancer Research    Mel Greaves   
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