Gene mutation linked to type of childhood cancer

25 October 2009

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Researchers have identified a gene that may play a role in the growth and spread of a childhood cancer called rhabdomyosarcoma, which develops in the body's soft tissues. The finding has revealed a potential new target for the treatment of this disease. The study, by scientists at the National Cancer Institute (NCI) and the National Heart, Lung and Blood Institute, components of the National Institutes of Health, and colleagues at The Children's Hospital in Westmead, Australia, and the Nationwide Children's Hospital, Columbus, Ohio, was published online 5 October 2009 in the Journal of Clinical Investigation.

Rhabdomyosarcoma (RMS) is the most common type of sarcoma found in children. This aggressive cancer can occur in many places in the body, but it usually begins in cells that form muscle tissue. Although progress has been made in increasing the overall survival of patients treated for RMS, less than 30 percent of children whose cancer has spread, or metastasised, survive more than five years.

The newly implicated gene produces a substance called fibroblast growth factor receptor 4, also referred to as FGFR4 protein. This protein belongs to a family known as receptor tyrosine kinases, which are involved in cellular signalling processes that help regulate cell growth, maturation, and survival, as well as the formation of new blood vessels. Mutations in receptor tyrosine kinase genes have been found previously in some other human cancers. Some of these mutations cause the tyrosine kinase to be active in the absence of an external signal that is normally required for activation, and this inappropriate activation may promote the development of cancer.

Earlier research by this team and others had shown that the FGFR4 gene is highly expressed in RMS tumours. The gene is also expressed during muscle development but not in mature muscle cells. Although this finding suggested a role for FGFR4 protein in RMS, the way in which it might contribute to the disease was not known.

In the new study, the team first examined FGFR4 gene expression in RMS tumours from patients for whom clinical follow-up data was available. The researchers found that high levels of FGFR4 gene expression were associated with advanced disease, including metastasis, as well as poor patient outcome. They next used genetic manipulation techniques to block the expression of the FGFR4 gene in human RMS cells. Suppression of FGFR4 gene expression slowed the growth of the cells in laboratory experiments. In addition, when these cells were transplanted into mice, they grew more slowly and were less likely to spread to the lungs than cells with unsuppressed FGFR4 genes.

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