Identification of genetic risk associated with prostate cancer using ancestry informative markers.

BACKGROUND: Prostate cancer (PCa) is a common malignancy and a leading cause of cancer death among men in the United States with African-American (AA) men having the highest incidence and mortality rates. Given recent results from admixture mapping and genome-wide association studies for PCa in AA men, it is clear that many risk alleles are enriched in men with West African genetic ancestry. METHODS: A total of 77 ancestry informative markers (AIMs) within surrounding candidate gene regions were genotyped and haplotyped using Pyrosequencing in 358 unrelated men enrolled in a PCa genetic association study at the Howard University Hospital between 2000 and 2004. Sequence analysis of promoter region single-nucleotide polymorphisms (SNPs) to evaluate disruption of transcription factor-binding sites was conducted using in silico methods. RESULTS: Eight AIMs were significantly associated with PCa risk after adjusting for age and West African ancestry. SNP rs1993973 (intervening sequences) had the strongest association with PCa using the log-additive genetic model (P=0.002). SNPs rs1561131 (genotypic, P=0.007), rs1963562 (dominant, P=0.01) and rs615382 (recessive, P=0.009) remained highly significant after adjusting for both age and ancestry. We also tested the independent effect of each significantly associated SNP and rs1561131 (P=0.04) and rs1963562 (P=0.04) remained significantly associated with PCa development. After multiple comparisons testing using the false discovery rate, rs1993973 remained significant. Analysis of the rs156113-, rs1963562-rs615382l and rs1993973-rs585224 haplotypes revealed that the least frequently found haplotypes in this population were significantly associated with a decreased risk of PCa (P=0.032 and 0.0017, respectively). CONCLUSIONS: The approach for SNP selection utilized herein showed that AIMs may not only leverage increased linkage disequilibrium in populations to identify risk and protective alleles, but may also be informative in dissecting the biology of PCa and other health disparities.

p53 Pro72Arg polymorphism and prostate cancer in men of African descent.

BACKGROUND: p53 is a transcription factor that regulates the cell cycle, DNA repair, and apoptosis. A variant at codon 72, rs1042522, results in altered activities for p53 and is, notably, differentially distributed among different ethnic populations. However, associations of this variant with cancer in men of African descent have not been explored. Herein, we tested the hypothesis that rs1042522 was associated with prostate cancer (PCa) risk. MATERIALS AND METHODS: Genotypes were determined by PCR-RFLP methods in a study population of African descent consisting of 266 PCa patients and 196 male controls. RESULTS: Our results indicate that the p53 polymorphism may be associated with increased risk of PCa. Genotypes were significantly and marginally associated with PCa risk using the dominant and log-additive genetic models (OR=1.53, 95% CI: 1.02-2.29, P=0.04; OR=1.33, 95% CI: 0.99-1.78, P=0.06, respectively). After adjusting for age, the associations with PCa remained, but results were not statistically significant (OR=1.48, 95% CI: 0.95-2.31, P=0.08; OR=1.30, 95% CI: 0.95-1.80, P=0.10, respectively). CONCLUSIONS: The present study demonstrates that population-dependent differences in allele frequencies associated with health disparities provide a valuable framework for the interrogation of complex diseases in all populations.

NAT2 and NER genetic variants and sporadic prostate cancer susceptibility in African Americans.

Prostate cancer is a common malignancy that disproportionately affects African-American men. Environmental factors and variation in genes responsible for chemical and dietary carcinogen metabolism and DNA damage repair may modulate risk. Fourteen single nucleotide polymorphisms in NAT2 and four NER genes (ERCC1, XPF/ERCC4, XPG/ERCC5 and CSB/ERCC6) were genotyped in a case-control study of 254 African-American prostate cancer cases and 301 healthy controls from Washington, DC. Smoking status, BMI, age and genetic ancestry were included as covariates in the association analyses. We found that individuals homozygous for the XPG/ERCC5 -72C/T promoter polymorphism had a significant reduction in risk, for prostate cancer (OR=0.12; 95% CI=0.03-0.48). A haplotype trend regression test also revealed a protective effect for the haplotype bearing the T allele (P=0.003). In silica analyses suggest a functional implication for the promoter variant since it deletes a GCF transcriptional factor-binding site responsible for the downregulation of transcription. The protective effect of the promoter SNP on risk for prostate cancer was independent of smoking. In contrast, none of the SNPs typed for NAT2, ERCC1, ERCC4 and ERCC6 showed significant association with risk. Additional tests for genotype interactions were not significant. We note that there may be other factors, such as dietary exposures, which may modulate prostate cancer risk in combination with genetic variation within the NAT2 and NER genes. Our results, in combination with previous observations of LOH for ERCC5 in prostate tumors, provide further evidence for a role of XPG/ERCC5 in the etiology of prostate cancer.

Germline BCL-2 sequence variants and inherited predisposition to prostate cancer.

Apoptosis is an essential physiological process that regulates cellular proliferation. Here, we explored the effect of DNA sequence variation within the BCL-2 gene on prostate cancer susceptibility in three clinical populations, consisting of 428 African Americans, 214 Jamaicans and 218 European Americans. We observed a 70% reduced risk for prostate cancer among the European Americans who had possessed two copies of a promoter variant -938C/A. Additionally, common BCL-2 haplotypes appeared to influence prostate cancer risk; however, studies in larger data sets are needed to confirm our findings. Our data suggest that inherited BCL-2 variants may be associated with a decrease in prostate cancer susceptibility.

A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history.

BACKGROUND: The EphB2 gene was recently implicated as a prostate cancer (PC) tumour suppressor gene, with somatic inactivating mutations occurring in approximately 10% of sporadic tumours. We evaluated the contribution of EphB2 to inherited PC susceptibility in African Americans (AA) by screening the gene for germline polymorphisms. METHODS: Direct sequencing of the coding region of EphB2 was performed on 72 probands from the African American Hereditary Prostate Cancer Study (AAHPC). A case-control association analysis was then carried out using the AAHPC probands and an additional 183 cases of sporadic PC compared with 329 healthy AA male controls. In addition, we performed an ancestry adjusted association study where we adjusted for individual ancestry among all subjects, in order to rule out a spurious association due to population stratification. RESULTS: 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 231 European American (EA) control samples. We observed that the 3055A-->T mutation significantly increased risk for prostate cancer over twofold (Fisher's two sided test, p = 0.003). The T allele was significantly more common among AAHPC probands (15.3%) than among healthy AA male controls (5.2%) (odds ratio 3.31; 95% confidence interval 1.5 to 7.4; p = 0.008). The ancestry adjusted analyses confirmed the association. CONCLUSIONS: Our data show that the K1019X mutation in the EphB2 gene differs in frequency between AA and EA, is associated with increased risk for PC in AA men with a positive family history, and may be an important genetic risk factor for prostate cancer in AA.

Clinical characteristics of African-American men with hereditary prostate cancer: the AAHPC Study.

INTRODUCTION: The African-American Hereditary Prostate Cancer (AAHPC) Study was designed to recruit African-American families fulfilling very stringent criteria of four or more members diagnosed with prostate cancer at a combined age at diagnosis of 65 years or less. This report describes the clinical characteristics of a sample of affected AAHPC family members. METHODS: In all, 92 African-American families were recruited into the study between 1998 and 2002. Complete clinical data including age and PSA at diagnosis, number of affected per family, stage, grade, and primary treatment were available on 154 affected males. Nonparametric Wilcoxon two-sample tests and Fisher's exact test (two-tailed), were performed to compare families with 4-6 and >6 affected males with respect to clinical characteristics. RESULTS: The mean number of affected men per family was 5.5, with a mean age at diagnosis of 61.0 (+/-8.4) years. Age at diagnosis, PSA and Gleason score did not show significant differences between the two groups of families. Based on the Gleason score, 77.2% of affected males had favorable histology. Significantly, there were marked differences between the two groups in the frequency of node-positive disease (P=0.01) and distant metastases (P=0.0001). Radical prostatectomy was the preferred primary therapy for 66.2% of all affected men followed by 20.8% who chose radiation therapy. CONCLUSIONS: Our findings suggest that affected males who carry the highest load of genetic factors are at the highest risk for early dissemination of disease, thus efforts at early diagnosis and aggressive therapeutic approaches may be warranted in these families. Since the primary therapy choices in our study favored definitive treatment (87.0%) when compared to the 1983 and 1995 SEER data in which 28 and 64% received definitive treatment, respectively, it appears that affected African-American men in multiplex families may be demonstrating the reported psycho-social impact of family history on screening practices and treatment decisions for prostate cancer.

Cyp17 promoter variant associated with prostate cancer aggressiveness in African Americans.

Androgens play an important role in the etiology of prostate cancer. The CYP17 gene encodes the cytochrome P450c17alpha enzyme, which is the rate-limiting enzyme in androgen biosynthesis. A T to C polymorphism in the 5' promoter region has recently been associated with prostate cancer. However, contradictory data exists concerning the risk allele. To investigate further the involvement of the CYP17 variant with prostate cancer, we typed the polymorphism in three different populations and evaluated its association with prostate cancer and clinical presentation in African Americans. We genotyped the CYP17 polymorphism in Nigerian (n = 56), European-American (n = 74), and African-American (n = 111) healthy male volunteers, along with African-American men affected with prostate cancer (n = 71), using pyrosequencing. Genotype and allele frequencies did not differ significantly across the different control populations. African-American men with the CC CYP17 genotype had an increased risk of prostate cancer (odds ratio, 2.8; 95% confidence interval, 1.0-7.4) compared with those with the TT genotype. A similar trend was observed between the homozygous variant genotype in African-American prostate cancer patients and clinical presentation. The CC genotype was significantly associated with higher grade and stage of prostate cancer (odds ratio, 7.1; 95% confidence interval, 1.4-36.1). The risk did not differ significantly by family history or age. Our results suggest that the C allele of the CYP17 polymorphism is significantly associated with increased prostate cancer risk and clinically advanced disease in African Americans.

African-American heredity prostate cancer study: a model for genetic research.

A genome-wide scan of high-risk prostate cancer families in North America has demonstrated linkage of a particular marker to Chromosome 1q (HPC1). An even greater proportion of African-American families have shown linkage to HPC1. Therefore, investigators at the National Human Genome Research Institute (NHGRI) in collaboration with Howard University and a predominantly African-American group of urologists established the African-American Hereditary Prostate Cancer (AAHPC) Study Network to confirm the suggested linkage of HPC in African Americans with a gene on Chromosome 1. Blood samples from recruited families were sent to Howard University for extraction of DNA. The DNA was sent to NHGRI at NIH where the genotyping and genetic sequence analysis was conducted. Genotype data are merged with pedigree information so that statistical analysis can be performed to establish potential linkage. From March 1, 1998, to June 1, 1999, a total of 40 African-American families have been recruited who met the study criteria. Preliminary results suggest that racial/ethnicity grouping may affect the incidence and extent of linkage of prostate cancer to specific loci. The importance of these findings lays in the future treatment of genetic-based diseases.

African-American heredity prostate cancer study: a model for genetic research.

A genome-wide scan of high-risk prostate cancer families in North America has demonstrated linkage of a particular marker to Chromosome Iq (HPC11. An even greater proportion of African-American families have shown linkage to HPC 1. Therefore, investigators at the National Human Genome Research Institute [NHGRI] in collaboration with Howard University and a predominantly African-American group of urologists established the African-American Hereditary Prostate Cancer (AAHPC) Study Network to confirm the suggested linkage of HPC in African Americans with a gene on Chromosome 1. Blood samples from recruited families were sent to Howard University for extraction of DNA. The DNA was sent to NHGRI at NIH where the genotyping and genetic sequence analysis was conducted. Genotype data are merged with pedigree information so that statistical analysis can be performed to establish potential linkage. From March 1, 1998, to June 1, 1999, a total of 40 African-American families have been recruited who met the study criteria. Preliminary results suggest that racial/ethnicity grouping may affect the incidence and extent of linkage of prostate cancer to specific loci. The importance of these findings lays in the future treatment of genetic-based diseases.

Recruitment experience in the first phase of the African American Hereditary Prostate Cancer (AAHPC) study.

The African American Hereditary Prostate Cancer (AAHPC) Study is an ongoing multicenter genetic linkage study organized by Howard University and the National Human Genome Research Institute (NHGRI), with support from the Office for Research on Minority Health and the National Cancer Institute. The goals of the study are to: (i) look for evidence of involvement of chromosome 1q24-25 (HPC1) in African American men with hereditary prostate cancer (HPC) and (ii) conduct a genome-wide search for other loci associated with HPC in African American men. To accomplish these goals, a network has been established including Howard University, the NHGRI, and six Collaborative Recruitment Centers (CRCs). The CRCs are responsible for the identification and enrollment of 100 African American families. To date, 43 families have been enrolled. Recruitment strategies have included mass media campaigns, physician referrals, community health-fairs/prostate cancer screenings, support groups, tumor registries, as well as visits to churches, barber shops, and universities. By far, the most productive recruitment mechanisms have been physician referrals and tumor registries, yielding a total of 35 (81%) families. Approximately 41% (n = 3400) of probands initially contacted by phone or mail expressed interest in participating; the families of 2% of these met the eligibility criteria, and 75% of those families have been enrolled in the study, indicating a 0.5% recruitment yield (ratio of participants to contacts). As the first large-scale genetic linkage study of African Americans, on a common disease, the challenges and successes of the recruitment process for the AAHPC Study should serve to inform future efforts to involve this population in similar studies.

Disease-free and overall survival after cryosurgical monotherapy for clinical stages B and C carcinoma of the prostate: a 20-year followup.

PURPOSE: We attempt to provide insight into the historical efficacy of cryosurgical monotherapy for prostate carcinoma through a single institution, retrospective, long-term followup. MATERIALS AND METHODS: From 1973 to 1977, 66 men underwent cryosurgical monotherapy for prostate carcinoma. Patient charts were reviewed to determine age, clinical stage, tumor grade, and progression-free, overall and cause specific survival status. RESULTS: Of 51 patients 47 to 81 years old (mean age 67.2) with clinically localized carcinoma 11 had clinical stage B and 40 had stage C disease. Tumor grade was well differentiated in 11 cases, moderately differentiated in 26, poorly differentiated in 11 and undetermined in 3. Recurrence was documented in 40 of the 51 men (78.4%) as local in 34 and unspecified in 6. Following recurrence all patients were treated with adjuvant therapy. All but 2 patients were followed until death with a mean followup of 93.7 months. Of the 51 men 24 (47.1%) died of disease and 17 (33.3%) died of an unspecified cause. Kaplan-Meier analysis demonstrated median overall progression-free survival of 34 months and median overall survival of 75 months. Median progression-free survival by grade was 34 months for well differentiated, 36 for moderately differentiated and 14 for poorly differentiated disease (p = 0.0288), and 57 for stage B and 30 for stage C disease (p = 0.0377). Median overall survival by grade was 114 months for well differentiated, 80 for moderately differentiated and 82 for poorly differentiated disease (p = 0.4437), and 60 months for stage B and 78.5 for stage C disease (p = 0.4915). CONCLUSIONS: As performed in this series cryosurgery was poorly effective for local control of prostatic carcinoma. Stage and grade correlated with the duration of tumor response but not with overall survival.

Cellular adhesion molecules in urologic malignancies.

Cell adhesion molecules (CAMs) are important in cell-cell interaction and interactions between cells and components of the extracellular matrix. CAMs have been associated with invasion and metastasis in a wide variety of human malignancies, including tumors of the genitourinary tract. Cadherins are transmembrane glycoproteins that bind cells by homophilic, homotypic interactions. Loss of expression of E-cadherin has been associated with dedifferentiation, invasion, and metastasis in prostate cancer and transitional cell neoplasia of the urinary bladder. CD44, a family of transmembrane glycoproteins principally involved in cell-extracellular matrix interactions, also has been associated with invasion and metastasis in urologic malignancies. Through alternative splicing, a variety of CD44 isoforms can be expressed that can undergo extensive posttranslational modification. CD44 variants have been associated with metastasis in a variety of human malignancies, particularly in the gastrointestinal system. Although loss of expression of CD44 standard form has been associated with aggressive prostate gland and bladder cancers, no specific isoform has been associated with metastasis of these neoplasms. Integrins are transmembrane glycoproteins with wide cellular distribution that bind a variety of extracellular matrix components. Integrins have been studied extensively in prostate cancer in which altered integrin expression has been associated with malignant prostatic epithelium. Additional adhesion molecules that have been studied to a variable degree in urologic malignancies include selectins and the immunoglobulin super-family. CAMs are fundamental to diverse biologic processes and appear capable of regulating intracellular signaling events that appear to have significant importance in human malignancy, including cancers of the urogenital tract.