© 1998 by Oxford University Press
Journal Of The National Cancer Institute, Vol 90, 1225-1229, Copyright © 1998 by Oxford University Press
TR Rebbeck, JM Jaffe, AH Walker, AJ Wein and SB Malkowicz
BACKGROUND: Pathways involved in androgen metabolism have been implicated
in the etiology of prostate cancer. The goal of this study was to evaluate
the effect of CYP3A4, a gene associated with the oxidative deactivation of
testosterone, on the clinical presentation of prostate cancers. METHODS: A
polymerase chain reaction-based approach was used to identify sequence
variants of the human CYP3A4 gene. To ascertain whether allelic variants of
the CYP3A4 gene were associated with tumor stage and grade and age of the
patient at diagnosis, we determined CYP3A4 genotypes in 230 Caucasian men
with incident prostate cancer. RESULTS: We identified a novel genetic
variant (CYP3A4-V) that has an altered 5' regulatory element, containing an
A to G mutation, upstream of the CYP3A4 gene. We then compared clinical
characteristics of prostate cancers in men who did and did not carry this
variant. The presence of the CYP3A4-V allele was associated with a higher
tumor- lymph node-metastasis (TNM) stage and Gleason grade. The association
between CYP3A4 genotype and tumor stage was most pronounced in men
diagnosed at a relatively old age who reported no family history of
prostate cancer. In this group, 46% of men with stage T3/T4 tumors carried
CYP3A4-V, whereas only 5% of individuals with stage T1 tumors carried
CYP3A4-V (adjusted odds ratio = 9.45; 95% confidence interval = 2.54-35.17;
chi2(1) = 12.28; two-sided P<.001). CONCLUSIONS: We determined that a
single base change in the 5' flanking region of the CYP3A4 gene was
associated with higher clinical stage and grade in men with prostate
tumors. Our results suggest that mutations in the CYP3A4 gene may influence
prostate carcinogenesis.
ARTICLES
Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4
Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia 19104-6021, USA. rebbeck@cceb.med.upenn.edu
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B. Amirimani, A. H. Walker, B. L. Weber, and T. R. Rebbeck RESPONSE: Re: Modification of Clinical Presentation of Prostate Tumors by a Novel Genetic Variant in CYP3A4 J Natl Cancer Inst, September 15, 1999; 91(18): 1588 - 1590. [Full Text] [PDF]
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