Characterization of FGFR4 mutations in Rhabdomyosarcoma

横纹肌肉瘤（RMS）是一种罕见的儿童软组织肉瘤， 肺泡（ARMS）或胚胎组织学亚型。在老年患者中观察到ARMS 并与染色体易位有关，产生了一个融合基因，涉及FOXO 1A， 13号染色体和PAX基因家族的成员。胚胎RMS的特点是年轻 诊断时的年龄、杂合性丢失和基因组印记模式改变1。一个 所有RMS组织学亚型长期生存率差的重要决定因素是 存在转移性疾病。导致肿瘤进展和转移的因素 疾病还不太清楚。基因表达模式的分析已经导致了改善的 肿瘤识别的准确性和肉瘤生物学的进展，特别是新的见解 转移调节器的可能机制。我们和其他人此前曾报道， FGFR 4，成纤维细胞生长因子受体（FGFR）的受体酪氨酸激酶（RTK）成员 基因家族，在RMS中高度表达，并且mRNA表达与蛋白水平相关。 这些观察结果表明，FGFR 4可能是肿瘤特异性诊断标志物和/或肿瘤特异性标志物。 肿瘤生物学的决定因素。在其他人类癌症中，存在一种常见的多态性， 编码区（FGFR 4 G388 R）与肿瘤细胞运动性和预后增加相关 在肉瘤、结肠癌或乳腺癌患者中。FGFR基因在以下方面引起了极大的兴趣： 癌症生物学，因为它们调节包括细胞存活在内的基本过程， 运动、发育和血管生成9. FGFR编码区的比较表明， FGFR 1、FGFR 2、FGFR 3和FGFR 4中的高氨基酸保守性区段。种系突变 在这些旁系同源中，已经描述了几种罕见的，高度渗透的Medelian疾病， 包括Crouzon综合征、Pfeiffer综合征和软骨发育不良。体细胞突变 在胶质母细胞瘤中的FGFR TK结构域中观察到了相同的同源物位点 多形性癌、乳腺癌、肺癌和子宫内膜癌。这些观察使我们 假设FGFR 4的激活，可能是由体细胞突变事件引起的， RMS、肉瘤或其他癌症的致癌过程。此外，FGFR 4过度活性 可能与晚期疾病和不良结局有关。

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.