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，通常分为肺泡（ARMS）或胚胎组织学亚型。ARMS在老年患者中观察到，与染色体易位有关，产生了一个融合基因，涉及13号染色体上的FOXO1A和PAX基因家族成员。胚胎性RMS的特点是诊断时较年轻，杂合性丧失和基因组印记模式改变1。所有RMS组织学亚型长期生存不良的一个重要决定因素是转移性疾病的存在。促进肿瘤进展和转移性疾病的因素尚不清楚。基因表达模式的分析提高了肿瘤鉴定的准确性和肉瘤生物学的进展，特别是对转移调节因子可能机制的新见解。我们和其他人之前报道过FGFR4，成纤维细胞生长因子受体（FGFR）基因家族的受体酪氨酸激酶（RTK）成员，在RMS中高表达，mRNA表达与蛋白水平相关。这些观察结果表明，FGFR4可能是肿瘤特异性诊断标志物和/或肿瘤生物学的决定因素。在其他人类癌症中，编码区（FGFR4 G388R）中常见多态性的存在与肉瘤、结肠癌或乳腺癌患者肿瘤细胞活力增加和预后相关。FGFR基因在癌症生物学中引起了极大的兴趣，因为它们调节包括细胞存活、运动、发育和血管生成在内的基本过程。FGFR编码区比较表明，FGFR1、FGFR2、FGFR3和FGFR4中存在氨基酸高度保守的片段。这些类似的种系突变已被描述为几种罕见的，高渗透的中代疾病，包括Crouzon综合征，Pfeiffer综合征和软骨发育不全。在多形性胶质母细胞瘤、乳腺癌、肺癌和子宫内膜癌中，已经观察到FGFR TK结构域的同源部位的体细胞突变。这些观察结果使我们假设FGFR4激活，可能是通过体细胞突变事件，可能对RMS、肉瘤或其他癌症的致癌过程至关重要。此外，FGFR4过活性可能与晚期疾病和不良预后相关。

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.