UICC World Cancer Congress 2006

The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program reported prostate cancer (PCa) age-adjusted incidence rates (per 100,000) of 274.3 among African American men (AAM) during the period 1997-2001 as compared with 171.2 among Caucasian men (CM), 60% higher among AAM vs. CM. Deaths from PCa are 2-3 times greater among AAM compared to CM. Age-adjusted mortality rates (per 100,00) over the period 1997-2001 were 70.4 among AAM and 29.8 among CM (NCI, SEER Cancer Stats, 2004). PCa mortality rates have decline over the last seven years 3.7% per year for CM and 2.3% for AAM, indicating increasing racial disparity (NCI, SEER Cancer Stats, 2004). Even though there is no strong evidence that prostate-specific antigen (PSA) testing reduces mortality, there is agreement that it has made substantial contributions to the reduction of metastatic PCa and stage shifting to early PCa. At Wayne State University (WSU), men undergoing radical prostatectomy have demonstrated a stage shift from 38% to 67% pathologically organ confined PCa among AAM and 51% to 71% for CM from the early nineties (1990-1995) to the late nineties (1996-2000). In the early nineties, when PCa was often diagnosed at a more advanced stage, there was a significant difference in recurrence or progression free-survival outcome between AAM vs CM, but in the late nineties that difference was eliminated (Bianco et. al., J. of Urology 2002). Thompson, et. al., JNCI, 2001, have reported that AAM experience a relatively poor survival outcome when AAM and CM men are treated similarly for metastatic PCa with hormonal therapy in a multi-center trial. These findings suggest that there is a racial disparity in survival outcome for men diagnosed with advanced PCa. An autopsy study of men who died from causes other than PCa conducted at Wayne State University, Detroit, MI, has reported that PCa begins at early ages (20-29) and that there is no differences in the distribution of PCa between AAM and CM. In another study of the Southeast Michigan SEER registry of men between the ages of 40-59, the distribution of distant PCa was 3 to 1, AAM to CM. Therefore, if PCa begins at equal percentages between AAM and CM but reaches distant PCa at a proportion of 3 to 1 in favor of AAM, it suggests that the cancer is growing faster among AAM compared to CM. We hypothesize that genetic and epigenetic factors are responsible for this phenomenon. We have examined some genetic factors that may be partly responsible for the increased incidence and more rapid growth of PCa among AAM vs. CM.

Prostate Cancer is an androgen sensitive disease. Cytochrome P450 3A4 (CYP3A4) oxidatively deactivates testosterone by converting it to biologically less active metabolites. Previous studies suggest that a germline genetic variant in the 5' regulatory region of the gene may interfere with deactivation and increase the risk of clinically advanced prostate cancer. (Rebbeck et. al., Cancer, Epid. Biomarker Prev., 1999). We investigated the impact of this polymorphism on the risk of recurrence after prostatectomy in a diverse population. There was a strong association between race and genotype (p=0.00002) in that 8% of CM and 83% AAM had 1 or more copies of the variant G allele. Unstratified analyses of men of both races and stratified analyses of CM demonstrated poorer progression free survival after prostatectomy for those with the variant G-allele.

A recent study was conducted in Southeast Michigan to investigate associations between prostate cancer and prostatitis and other risk factors in a case-control study. Prostate cancer was found to be associated with prostatitis. (Patel et al, Cancer Causes Control, Apr. 2005). A model of chronic inflammation to carcinogenesis has been reported. In response to infection, phagocytic cells generated bacteriocidal reactive oxygen (superoxides) and nitrogen (e.g. macrophage, nitric oxides) species that damage DNA. Therefore, inflammation may be an initiator, via genotoxic effects, and a promoter, via cytotoxic effects, of carcinogenesis (Coussens et.al., Nature 2002 & Platz et.al, J. of Urology, 2004). MSR-1 (Macrophage Scavenger Receptor) gene maps to 8p 22-23 and encodes a cell surface scavenger receptor (SR-A protein) that facilitates macrophage uptake of a wide range of ligands. Xu et al. Amer. J. Human Genet, 2003, identified 5 common variants in patients with non-hereditary prostate cancer. We examined the variants among men who have undergone radical prostatectomy to evaluate racial distribution and the effect of these variants on PCa progression after prostatectomy. The results will be discussed.

The African American Hereditary Prostate Cancer (AAHPC) consortium have recruited more than 100 families to identify candidate genes responsible for hereditary prostate cancer among AAM. We have recently reported our first genetic findings: common nonsense mutation in the EphB2 gene on Chromosome 1p, associated with PCa risk in AAM with a positive family history. (Kittles et. al., J of Medical Genetics, 2005) Ten coding sequence variants were identified, including the K1019x (3055A>T) nonsense mutation which was present in 15.3% of the AAHPC probands but only 1.7% of CM control samples. We observed that the 3055A>T mutation significantly increased risk of PCa over two fold (Fisher's 2-sided p=0.003). Summary 1. There is increasing evidence of biologic/genetic differences associated with ethnicities or geographic origin of specific populations. 2. The evidence suggest that there are multiples biologic/genetic pathways to the phenotypic expression and progression of PCa. 3. The role that biologic/genetic factors play in clinical outcome is being defined. 4. More research is needed.