Involvement of the FGFR4 Arg388 allele in head and neck squamous cell carcinoma

Abstract

After decades of rigorous investigations of chemotherapeutic cancer therapies, many cancers, including those of the head and neck, remain beyond our clinical ability to control them. From 3% to 5% of all patients initially cured of early-stage head and neck cancer will develop second primary tumors or local recurrences. 1 This phenomenon has been explained by the concept of field cancerization, which argues that certain risk factors such as alcohol and tobacco change the lining of the upper aerodigestive tract into a so-called condemned mucosa. In such a scenario, alcohol may represent the key risk factor for neoplastic transformation in the oral cavity, the oro-and hypopharynx. [2][3][4] An increasing amount of evidence suggests that alcohol intake and smoking play a synergistic role in the neoplastic progress.One of the most important achievements of molecular oncology has been the demonstration that cancer represents a genetic disease that begins with genetic damages in the genome of one cell in the form of point mutations, DNA rearrangement and gene amplification leading to the distortion of the expression and biochemical function of respective gene products. Growth factor receptors of the class I subfamily, which include the epidermal growth factor receptor (EGFR/HER1) and the related proteins HER2, HER3 and HER4, have shown that amplification or overexpression of those receptors, especially well documented for HER2 in patients with breast and ovarian cancers, plays an important role in carcinogenesis and tumor progression. [5][6][7][8] Multivariate survival analysis showed that HER2 amplification or overexpression is more predictive of clinical outcome than all other known prognosticators with the exception of positive lymph nodes. 9,10 These findings have validated the HER2 receptor as a target for therapeutic intervention. Moreover, recent clinical investigations have confirmed the benefit of antagonistic HER2 antibody therapy in breast cancer using herceptin. 11 Minute genetic changes such as point mutations have been found to cause constitutive activation of the HER2/neu kinase activity and to induce neoplastic disorders. 12 Similarly, the 2 amino acid substitutions Gly380Arg and Ala391Glu in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) have been shown to be responsible for 2 forms of human dwarfism, namely, achondroplasia and morbus crouzon. [13][14][15] Other mutations in the FGFR3 gene have been associated with bladder and cervix cancer. 16 The FGFR signaling system is composed of 4 receptor tyrosine kinases (RTKs) and more than 20 known ligands and has been implicated in the regulation of a multitude of both physiologic and pathophysiologic processes, including migration, wound healing, angiogenesis and cancer. 17 More recently, we have identified a single nucleotide polymorphism (SNP) in codon 388 of the FGFR4 gene, which plays a pivotal role in the progression of breast cancer. This SNP is present at a significantly higher rate in breast cancer patients with early relap...

FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients

“…In accordance with previous studies, no correlation was found between the genotype and the protein expression of FGFR4 (Streit et al, 2004).…”

“…However, the Arg388 isotype was significantly overrepresented in the group of node-positive breast cancer patients with early relapse but not associated with a shortened disease-free survival in nodenegative breast cancer (Bange et al, 2002). Recently, Streit et al (2004) demonstrated an association between high expression of FGFR4 Arg388 allele and poor clinical outcome in head and neck squamous cell carcinoma (HNSCC). These findings were supported by independent groups with similar results in soft tissue sarcoma, prostate cancer and lung adenocarcinoma (Morimoto et al, 2003;Wang et al, 2004;Spinola et al, 2005).…”

Joint association of polymorphism of the FGFR4 gene and mutation TP53 gene with bladder cancer prognosis

“…A trend showed a better disease-specific survival rate for bladder cancer patients with the Arg/Arg genotype. This is contrary to the findings of previous studies on other types of cancer that the presence of the Arg allele is associated with poor survival (Bange et al, 2002;Morimoto et al, 2003;Streit et al, 2004;Wang et al, 2004;Spinola et al, 2005a). The reason for the conflicting results is unclear, but may reflect a tissue-specific effect of this polymorphism.…”

“…A positive correlation between the presence of the FGFR4 Arg388 allele and prognostic parameters as well as survival time was reported in variant cancer studies, including breast, colon, lung, prostate, head and neck cancers and high-grade soft-tissue sarcoma (Bange et al, 2002;Morimoto et al, 2003;Streit et al, 2004;Wang et al, 2004;Spinola et al, 2005a).…”

Further observations on the relationship between the FGFR4 Gly388Arg polymorphism and lung cancer prognosis

“…Recently, a common polymorphism in the transmembrane domain of the FGFR4 gene, Gly388Arg, has been reported to correlate with tumour aggressiveness (lymph node metastasis, advanced stage at presentation and reduced survival in several cancer types, including breast, sarcoma, lung and prostate (Bange et al, 2002;Morimoto et al, 2003;Nakamura et al, 2004;Wang et al, 2004;Spinola et al, 2005a)). Some of these studies were, however, conducted on relatively small sample sizes and subsequent studies of breast, colon, head and neck, and bladder cancers (Becker et al, 2003;Jezequel et al, 2004;Streit et al, 2004;Spinola et al, 2005b;Yang et al, 2006), have provided little support for an association between FGFR4 Gly388Arg genotype and prognosis.To evaluate the prognostic significance of the FGFR4 Gly388Arg polymorphism in lung cancer, we analysed a cohort of 619 lung cancer patients. We employed a comprehensive set of statistical tests, including those sensitive to detecting differences in early survival.…”