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The Fibroblast Growth Factor Receptor-4 Arg³⁸⁸ Allele Is Associated with Prostate Cancer Initiation and Progression

Departments of ¹ Pathology and ² Molecular and Human Genetics, Baylor College of Medicine; and ¹ Michael E. DeBakey Department of Veterans Affairs Medical Center, Houston, Texas

Purpose: Increased expression of fibroblast growth factors that can activate the fibroblast growth factor receptor-4 (FGFR-4) occurs in a substantial fraction of human prostate cancers in vivo. A germline polymorphism of the FGFR-4 gene resulting in expression of arginine at codon 388 (Arg³⁸⁸) is associated with aggressive disease in patients with breast and colon cancer. We therefore sought to determine whether the FGFR-4 Arg³⁸⁸ allele was associated with prostate cancer incidence and/or the occurrence of aggressive disease.

Experimental Design: The FGFR-4 genotype of men undergoing radical prostatectomy and controls of the same race was determined and the genotype correlated with clinical and pathologic markers of disease aggressiveness. PNT1A cell lines expressing predominantly the FGFR-4 Arg³⁸⁸ or Gly³⁸⁸ allele were established, and cell migration and invasiveness of these cells were assessed by a wounding assay and by quantitative determination of invasion through Matrigel. Expression of urokinase-type plasminogen activator receptor was determined by quantitative RT-PCR and enzyme-linked immunoabsorption assay.

Results: Homozygosity for the FGFR-4 Arg³⁸⁸ allele is strongly associated with the occurrence of prostate cancer in white men. The presence of the FGFR-4 Arg³⁸⁸ allele is also correlated with the occurrence of pelvic lymph node metastasis and biochemical (prostate-specific antigen) recurrence. Expression of FGFR-4 Arg³⁸⁸ in immortalized prostatic epithelial cells results in increased cell motility and invasion through Matrigel and was associated with increased expression of urokinase-type plasminogen activator receptor.

Conclusion: The FGFR-4 Arg³⁸⁸ allele is associated with both an increased incidence and clinical aggressiveness of prostate cancer and results in changes in cellular motility and invasiveness in immortalized prostate epithelial cells consistent with the promotion of metastasis.

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