Molecular Epidemiology

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The biology of prostate cancer is being examined in several studies, one of which includes racial or ethnic comparisons. Chromosome 8p studies demonstrate frequent alterations at several sites in prostate cancer, and it has been suggested that these changes may be "early" rather than "late" promotional events during prostate tumorigen-esis. More specifically, there is thought to be a prostate suppressor gene on chromosome 8p.

In 135 prostate cancers, Macoska et al. examined the correlation of 8p allelic loss with patients' ethnic origins. The tumors examined were from radical prostatectomy specimens that were matched for stage and grade. No significant differences between African American men and Caucasian men were observed in terms of fractional allelic loss frequencies among the three deletion domains, or total 8p loss. With regard to loss differences between individual 8p loci, the reported trends are unclear.44

One recent study was conducted to determine whether primary prostate cancers from African American and Caucasian men harbor different patterns or frequencies of chromosomal alterations. Comparative genomic hybridization (CGH) is a molecular cytoge-netic method that assays tumor tissue for somatic chromosomal gains and deletions. An advantage of this technique for a comparative ethnic study of tumor tissue is that the entire genome is examined. Surgical specimens from patients undergoing radical prostatectomy for clinically localized prostate cancer were processed in the pathology department immediately following surgery. Pathologic stage groupings were comparable between African American and Caucasian men. The most common Gleason score among the tumors studied was 7 out of 10. There was no detectable difference in the mean pre-operative serum PSA between the groups. It was con-

eluded that the region-specific frequencies of chromosomal alterations between the two groups of tumors were very similar across the vast majority of the genome. This study supports the concept that biologic differences must be explained by subtle genomic changes and not at the chromosomal level.45

Investigators from the National Human Genome Research Institute and Johns Hopkins University studied 91 high-risk prostate cancer families in North America and Sweden. Two of these families were African American. Of the 91 families studied, approximately 1 in 3 showed linkage to HPC1, including both of the African American families. Although the majority of subjects studied were not African Americans, sufficient evidence was obtained to suggest that hereditary prostate cancer (HPC) in African Americans is linked to a locus on chromosome 1.46

In a recent update of this study, African Americans were shown to have two times greater prevalence of prostate cancer linkage to HPC1 than Caucasians.47 Recently, Cooney et al. confirmed that chromosome 1q 24-25 is likely to contain a prostate cancer susceptibility gene. The six African American families in their study contributed disproportionally to the observation of linkage.48 There is currently a larger study underway to recruit African American families to further substantiate the correlation of HPC in African American men with a gene on chromosome 1.

Prostate cell division is controlled by testosterone after intracellular conversion to its reduced form, dihy-drotestosterone, by 5 alpha-reductase. Ross and others have found evidence suggesting that racial or ethnic variations in prostate cancer are due in part to underlying differences in androgen secretion and metabolism. Young adult African American men have at least 10% higher circulating testosterone levels than do young adult Caucasian men. This difference, if sustained over an extended period, is probably sufficient to explain the 60 to 70% higher prostate cancer rates in older adult African Americans compared to Caucasians.49 The authors further report that African American women have much higher first-trimester testosterone levels than do Caucasian women.50 They speculate that these high testosterone levels contribute to high rates of prostate cancer in male offspring, possibly by their impact on the hypothalamic-pituitary-testicular feedback system, the gonadostat, causing higher circulating levels of testosterone. This evidence is consistent with the higher prevalence of highgrade PIN noted in autopsy studies performed by Sakr et al.15 High-grade PIN depends on androgen circulation.

Shorter androgen receptor CAG (glutamine) repeat length may be associated with increased risk of developing prostate cancer.51 It has been demonstrated that shorter CAG repeats are associated with increased androgen stimulation and the diagnosis of prostate cancer at a younger age.52 It has also been reported that African

American men have a greater percentage of short CAG repeats on the androgen receptor gene than do American Caucasian men.53 Thus, there are several hormonal factors as well as other genetic factors that may help explain the increased incidence of clinically significant prostate cancer among African American men compared to Caucasian men. Further research in these areas is needed.

Environmental factors such as diet or other epigenetic factors may play a significant role in explaining racial or ethnic differences in prostate cancer. Accumulating evidence indicates that a diet high in fat content is closely associated with prostate cancer progression.1 Observation and preliminary evidence suggest that African Americans consume a diet high in fat content. It has been postulated that diet can alter steroid hormone profiles and therefore modify prostate cancer risk throughout life.2 If this is true, as Ross and Henderson suggest, diet regulated hormonal influences first occur in utero. This may explain why African American women have much higher first-trimester testosterone levels than do Caucasian women and helps account for the high risk of prostate cancer among African American men.54

It has been shown that 12 (S)-hydroxyeicosatetaraenoic acid (12 [S]-HETE), the metabolite of arachidonic acid (a free fatty acid), enhances the invasiveness and metastatic potential of prostate cancer cells.3 The enzyme responsible for 12 (S)-HETE biosynthesis is 12-lipoxygenase, which may therefore be a prognostic marker for aggressive prostate cancer.

Preliminary data examining the correlation of race, age, stage, and 12-lipoxygenase mRNA expression indicate a greater percentage of elevated 12-lipoxygenase expression among African American versus Caucasian men with stage T2 or T3 prostate cancer. More importantly, among patients 51 to 60 years old, 56% (5 of 9) African American men and 19% (3 of 16) Caucasian men had increased expression of 12-lipoxygenase mRNA.3 The small sample size may account for the lack of apparent difference.

Alice Whittemore and others have also studied prostate cancer in relation to diet among African Americans, Caucasians, and Asians in the United States and Canada. She noted a positive statistically significant association of prostate cancer risk and total fat intake among all ethnic groups combined. This association was attributable to energy from saturated fats; after adjusting for saturated fat, risk was associated only weakly with monounsaturated fat and was unrelated to protein, carbohydrates, polyunsatu-rated fat, and total food energy. Fat intake and the percentage of energy from fat also differed appreciably among different ethnicities; they were highest in African Americans, followed by Caucasian Americans, Japanese Americans, and Chinese Americans. Similar ethnic differences were seen in the consumption of red meats. However, crude estimates suggest that the differences in saturated fat intake account for about 10% of black versus white differences in prostate cancer incidence. These investigators suggested that their data support a causal role in prostate cancer for saturated fat intake but suggest that other factors are largely responsible for interethnic differences in risk.2

Giovannucci et al. recently reported on the dietary intake between 1986 and 1992 of 47,894 health professionals who were free of cancer. In this cohort, intake of lycopene or other compounds in tomato-based foods appeared to reduce prostate cancer risk, but other carotenoids measured were unrelated to prostate cancer risk. These researchers further demonstrated that African American men consumed tomato-based products infrequently and that their serum lycopene intake level was the lowest of all the ethnic groups studied. African American men also had the highest incidence of prostate cancer in this study population.55

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