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 Oct. 5, 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 metastasized, 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 signaling 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 tumors. 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 tumors 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.
The team next looked for mutations in the FGFR4 gene in 94 human RMS tumors obtained from the NCI-funded Cooperative Human Tissue Network and Children’s Hospital. They found that more than seven percent of the tumors had mutations causing alterations in the tyrosine kinase portion of the FGFR4 protein.
Four different mutations, two in each of two locations in the FGFR4 gene, were predicted to change the function of the FGFR4 protein. In laboratory studies, the researchers further investigated two of the mutations and found that both produced proteins that were able to promote their own activation, a hallmark of tyrosine kinase mutations that are associated with cancer. The mutations also appear to be involved in activation and suppression of cell signaling pathway components which have been associated with cell growth and survival in RMS and other cancers and with metastasis. Additionally, the researchers found that, when RMS cells had the mutations, they were more sensitive to treatment with drugs that inhibit FGFR4 activity. Thus, a mutated FGFR4 gene may represent an Achilles’ heel in RMS.
The researchers note their findings represent the first known mutations in a receptor tyrosine kinase in RMS. “Our study shows that, when FGFR4 is overactive, either due to increased expression or mutations, it plays a key role in the growth and spread of RMS and that this gene could be an important target for therapy,” said senior author Javed Khan, M.D., of NCI’s Center for Cancer Research. “It also emphasizes that high-risk or metastatic cancers may harbor other critical, as yet undiscovered, mutations. Therefore, we and others are applying advanced next-generation techniques to sequence the entire genome (DNA) to search for every mutation that may contribute to pediatric and other cancers, and thus discover potential targets for personalized or individualized treatment.”
For more information about Dr. Khan’s research, please go to http://ccr.nci.nih.gov/staff/staff.asp?profileid=5584.
For more information about rhabdomyosarcoma, please go to http://www.cancer.gov/cancertopics/types/childrhabdomyosarcoma.
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Reference: Taylor, JG, Cheuk AT, Tsang PS, Chung J, Song YK, Desai K, Yu Y, Chen Q, Shah K, Youngblood V, Fang J, Kim SY, Yeung C, Helman LJ, Mendoza A, Ngo V, Staudt LM, Wei JS, Khanna C, Catchpoole D, Qualman SJ, Hewitt SM, Merlino G, Chanock SJ, and Khan J. Identification of FGFR4 activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. Journal of Clinical Investigation. Online October 5, 2009.