Characterization of FGFR4 mutations in Rhabdomyosarcoma

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Rhabdomyosarcoma (RMS) is a rare pediatric soft tissue sarcoma typically classified as either alveolar (ARMS) or embryonal histological subtypes. ARMS is observed in older patients and is associated with a chromosomal translocation creating a fusion gene involving FOXO1A on chromosome 13 and members of the PAX gene family. Embryonal RMS is characterized by a younger age at diagnosis, loss of heterozygosity and altered patterns of genomic imprinting1. An important determinant of poor long term survival for all RMS histological subtypes is the presence of metastatic disease. Factors contributing to tumor progression and metastatic disease are not well understood. Analysis of gene expression patterns have led to improved accuracy of tumor identification and advances in sarcoma biology, particularly new insights into possible mechanisms of metastatic regulators. We and others have previously reported that FGFR4, a receptor tyrosine kinase (RTK) member of the fibroblast growth factor receptor (FGFR) gene family, is highly expressed in RMS and mRNA expression correlates with protein levels. These observations suggest that FGFR4 could be a tumor specific diagnostic marker and/or a determinant of tumor biology. In other human cancers, the presence of a common polymorphism in the coding region (FGFR4 G388R) is associated with increased tumor cell motility and prognosis in patients with sarcomas, colon or breast cancer. The FGFR genes are of great interest in cancer biology because they regulate essential processes including cellular survival, motility, development, and angiogenesis9. Comparison of the FGFR coding regions indicates segments of high amino acid conservation in FGFR1, FGFR2, FGFR3, and FGFR4. Germline mutations in these paralogs have been described for several rare, highly penetrant Medelian disorders including Crouzon syndrome, Pfeiffer syndrome, and hypochondroplasia. Somatic mutations at the same sites of paralologs have been observed within the FGFR TK domains in glioblastoma multiforme, breast cancer, lung cancer and endometrial carcinoma. These observations lead us to hypothesize that FGFR4 activation, perhaps by somatic mutational events, could be critical to the oncogenic process in RMS, sarcomas, or other cancers. Furthermore, FGFR4 over activity could be associated with advanced stage disease and poor outcome.