原文
Gene Mutation Linked To Type Of Childhood Cancer
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 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
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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 here.
For more information about rhabdomyosarcoma, please go here.
NCI leads the National Cancer Program and the NIH effort to dramatically reduce the
burden of cancer and improve the lives of cancer patients and their families, through
research into prevention and cancer biology, the development of new interventions,
and the training and mentoring of new researchers. For more information about cancer,
please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer
Information Service at 1-800-4-CANCER (1-800-422-6237).
Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute
(NHLBI) plans, conducts, and supports research related to the causes, prevention,
diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep
disorders. The Institute also administers national health education campaigns on
women and heart disease, healthy weight for children, and other topics. NHLBI press
releases and other materials are available online at: http://www.nhlbi.nih.gov.
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The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -includes 27 Institutes and Centers and is a component of the U.S. Department of
Health and Human Services. It is the primary federal agency for conducting and
supporting basic, clinical and translational medical research, and it investigates the
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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.
SOurce
National Institutes of Health
文摘
J Clin Invest. 2009 Oct 5. pii: 39703. doi: 10.1172/JCI39703
Identification of FGFR4-activating mutations in human rhabdomyosarcomas
that promote metastasis in xenotransplanted models
Vi JG, Cheuk AT, Tsang PS, Chung JY, Song YK, Desai K, Yu Y, Chen QR, 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,
Khan J.
Rhabdomyosarcoma (RMS) is a childhood cancer originating from skeletal muscle,
and patient survival is poor in the presence of metastatic disease. Few determinants
that regulate metastasis development have been identified. The receptor tyrosine
kinase FGFR4 is highly expressed in RMS tissue, suggesting a role in tumorigenesis,
although its functional importance has not been defined. Here, we report the
identification of mutations in FGFR4 in human RMS tumors that lead to its activation
and present evidence that it functions as an oncogene in RMS. Higher FGFR4
expression in RMS tumors was associated with advanced-stage cancer and poor
survival, while FGFR4 knockdown in a human RMS cell line reduced tumor growth
and experimental lung metastases when the cells were transplanted into mice.
Moreover, 6 FGFR4 tyrosine kinase domain mutations were found among 7 of 94
(7.5%) primary human RMS tumors. The mutants K535 and E550 increased
autophosphorylation, Stat3 signaling, tumor proliferation, and metastatic potential
when expressed in a murine RMS cell line. These mutants also transformed NIH 3T3
cells and led to an enhanced metastatic phenotype. Finally, murine RMS cell lines
expressing the K535 and E550 FGFR4 mutants were substantially more susceptible to
apoptosis in the presence of a pharmacologic FGFR inhibitor than the control cell
lines expressing the empty vector or wild-type FGFR4. Together, our results
demonstrate that mutationally activated FGFR4 acts as an oncogene, and these are
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what we believe to be the first known mutations in a receptor tyrosine kinase in RMS.
These findings support the potential therapeutic targeting of FGFR4 in RMS.
PMID: 19809159 [PubMed - as supplied by publisher]
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