Vitamin D Receptor Start Codon Polymorphism (FokI) and Prostate Cancer Progression

Vitamin D Receptor Start Codon Polymorphism (FokI) and Prostate Cancer Progression1

Departments of Urology [Y. X., J. E. M., T. A. S., D. M. P.], Health Research and Policy [A. S.], and Medicine [D. F.], Stanford University School of Medicine, Stanford, California 94305

Abstract

Vitamin D plays an important role in cell growth and differentiation and is proposed to protect against cancer initiation and/or progression. The vitamin D receptor (VDR) has a thymine/cytosine (T/C) polymorphism located in the first of two potential start (ATG) codons that can be detected by a RFLP using the endonuclease FokI. The C variant, which lacks the first ATG, results in a shorter VDR and is referred to as the F allele. The T variant (f allele) initiates at the first ATG. We examined the association of the VDR FokI genotype with histopathological characteristics and prognosis of prostate cancer among 191 mostly Caucasian subjects who had undergone radical prostatectomy between 1984 and 1992. The frequencies of the FF, Ff, and ff genotypes were 41%, 38%, and 21%, respectively. Subjects with the ff genotype had a lower mean percentage of Gleason grade 4/5 cancer (30.3%) than subjects with the FF or Ff genotypes (42.8% and 43.8%, respectively; P = 0.015 by t test for ff versus FF + Ff). The data suggest that the presence of an F allele increased the risk of being diagnosed with more aggressive cancer because higher percentage of Gleason grade 4/5 is associated with worse prognosis. The age-adjusted risk of prostate-specific antigen failure was lower for the ff genotype than for the FF genotype by Cox proportional hazards analysis but did not achieve statistical significance (hazard ratio = 0.76; 95% confidence interval, 0.44–1.32). This risk reduction disappeared after further adjustment for percentage of Gleason grade 4/5, cancer volume, and preoperative serum prostate-specific antigen level (hazard ratio = 1.03; 95% confidence interval, 0.58–1.85). In conclusion, the ff genotype was associated with less aggressive histopathological findings than Ff or FF genotypes. Additional studies with a larger sample size and investigation of the functional significance of the FokI polymorphism in prostate cancer cells are warranted.

Footnotes

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↵1 Supported by the Cancer Research Fund, under Interagency Agreement 97-12013 (University of California, Davis Contract 98-00924V) with the Department of Health Services, Cancer Research Section./. Mention of trade name, proprietary product or specific equipment does not constitute a guaranty or warranty by the Department of Health Services, nor does it imply approval to the exclusion of other products. The views expressed herein represent those of the authors and do not necessarily represent the position of the State of California, Department of Health Services.
↵2 To whom requests for reprints should be addressed, at Department of Urology, Stanford Medical Center, Stanford, CA 94305-5118. Phone: (650) 725-5531; Fax: (650) 723-0765; E-mail: dpeehl{at}stanford.edu
↵3 The abbreviations used are: PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; PSA, prostate-specific antigen; 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃; CI, confidence interval; HR, hazard ratio; VDR, vitamin D receptor.
- Accepted October 26, 1902.
- Received June 13, 1902.
- Revision received October 18, 1902.