Association between a CYP3A4 genetic variant and clinical presentation in African-American prostate cancer patients.

Prostate cancer incidence, clinical presentation, and mortality rates vary among different ethnic groups. A genetic variant of CYP3A4, a gene involved in the oxidative deactivation of testosterone, has been associated recently with prostate cancer development in Caucasians. To further investigate this variant, we evaluated its genotype frequencies in different ethnic groups and its association with clinical presentation of prostate cancer in African Americans. CYP3A4 genotypes were assayed in healthy male Caucasian (n = 117), Hispanic (n = 121), African-American (n = 116), Chinese (n = 46), and Japanese (n = 34) volunteers using the TaqMan assay. The association between CYP3A4 genotype and prostate cancer presentation was determined in 174 affected African-American men. Genotype frequency of the CYP3A4 variant differed substantially across ethnic groups, with African Americans much more likely to carry one or two copies than any other group (two-sided P < 0.0001). Among African Americans, 46% (80 of 174) of men with prostate cancer were homozygous for the CYP3A4 variant, whereas only 28% (32 of 116) of African-American healthy volunteers were homozygous (two-sided P < 0.005). A consistent positive association was observed between being homozygous for the CYP3A4 variant in African-American prostate cancer patients and clinical characteristics. Men homozygous for the CYP3A4 variant were more likely to present with higher grade and stage of prostate cancer in a recessive model [odds ratio (OR), 1.7; 95% confidence interval (CI), 0.9-3.4]. This association was even stronger for men who were >65 years of age at diagnosis (n = 103; OR, 2.4; 95% CI, 1.1-5.4). In summary, the CYP3A4 genotype frequency in different ethnic groups broadly followed trends in prostate cancer incidence, presentation, and mortality in the United States. African-American prostate cancer patients had a higher frequency of being homozygous for the CYP3A4 variant than healthy African-American volunteers who were matched solely based on ethnicity. Among the patients, those who were homozygous for the CYP3A4 variant were more likely to present with clinically more advanced prostate cancer.

[1]  T. Rebbeck.  Modification of Clinical Presentation of Prostate Tumors by a Novel Genetic Variant in CYP3A4 , 1999 .

[2]  M. Schell,et al.  Adjusted odds ratios under nondifferential misclassification: application to prostate cancer. , 1999, Journal of clinical epidemiology.

[3]  P. Nowell,et al.  Association of CYP3A4 genotype with treatment-related leukemia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[4]  A. Whittemore,et al.  Race, prostate cancer survival, and membership in a large health maintenance organization. , 1998, Journal of the National Cancer Institute.

[5]  D A Meyers,et al.  Major Susceptibility Locus for Prostate Cancer on Chromosome 1 Suggested by a Genome-Wide Search , 1996, Science.

[6]  K. Livak,et al.  Real time quantitative PCR. , 1996, Genome research.

[7]  K. Schwartz,et al.  Removal of the financial barrier to health care: does it impact on prostate cancer at presentation and survival? A comparative study between black and white men in a Veterans Affairs system. , 1995, Urology.

[8]  S. Tagawa,et al.  Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control. , 1993, European journal of biochemistry.

[9]  D. Gleason,et al.  Histologic grading of prostate cancer: a perspective. , 1992, Human pathology.

[10]  T. Aoyama,et al.  Steroid hormone hydroxylase specificities of eleven cDNA-expressed human cytochrome P450s. , 1991, Archives of biochemistry and biophysics.

[11]  D. Waxman,et al.  Human liver microsomal steroid metabolism: identification of the major microsomal steroid hormone 6 beta-hydroxylase cytochrome P-450 enzyme. , 1988, Archives of biochemistry and biophysics.

[12]  T. Rebbeck,et al.  Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Mutations in brief no. 191. Online. , 1998, Human mutation.

[13]  J. Kaufman,et al.  Androgens in male senescence , 1998 .

[14]  Taylor Murray,et al.  Cancer statistics, 1998 , 1998, CA: a cancer journal for clinicians.

[15]  G. A. Alexander,et al.  Racial/ethnic patterns of cancer in the United States, 1988-1992. , 1996 .