Search

Background: Recently, a novel HOXB13 variant (X285K) was observed in men of African descent with prostate cancer (PCa) in Martinique. Little is known about this or other variants in HOXB13 which may play a role in PCa susceptibility in African-American (AA) men., Methods: We sequenced HOXB13 in an AA population of 1048 men undergoing surgical treatment for PCa at Johns Hopkins Hospital., Results: Seven non-synonymous germline variants were observed in the patient population. While six of these variants were seen only once, X285K was found in eight patients. In a case-case analysis, we find that carriers of this latter variant are at increased risk of clinically significant PCa (1.2% carrier rate in Gleason Score ≥7 PCa vs. 0% in Gleason Score <7 PCa, odds ratio, OR = inf; 95% Confidence Interval, 95%CI:1.05-inf, P = 0.028), as well as PCa with early age at diagnosis (2.4% carrier rate in patients <50 year vs. 0.5% carrier rate in patients ≥50 year, OR = 5.25, 95% CI:1.00-28.52, P = 0.03)., Conclusions: While this variant is rare in the AA population (~0.2% MAF), its ancestry-specific occurrence and apparent preferential association with risk for the more aggressive disease at an early age emphasizes its translational potential as an important, novel PCa susceptibility marker in the high-risk AA population., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

African Americans are at increased risk of cancer and associated mortalities compared with European American populations. Socioeconomic, cultural, and biological factors have been implicated in this discrepancy. In this issue of the JCI, Piyarathna et al. identify a set of genes that are upregulated in a number of tumor types in African American cancer patients as compared with European American patients. These genes were associated with enhanced oxidative phosphorylation and upregulation of transcription factors that promote mitochondrial biogenesis, resulting in greater numbers of mitochondria in tumor samples from African American subjects. Together, these results indicate that mitochondria dysfunction may underlie the increased cancer incidence and poor outcomes observed in African American patients.

Background: African Americans have both a higher incidence of prostate cancer and greater disease-specific mortality compared with non-Hispanic whites. Historically, the investigation of the contribution of rare genetic variants to prostate cancer in African American men has been hampered by low participation in large genetic studies, particularly those focused on early-onset and familial disease., Methods: We sequenced 160 genes purported to be involved in carcinogenic pathways in germline DNA samples collected from 96 African American men diagnosed with early-onset prostate cancer (≤55 years at diagnosis). REVEL software was used to determine the pathogenic potential of observed missense variants., Results: We observed three protein-truncating mutations, one in BRCA2 and two in BRIP1 in three African American men diagnosed with early-onset prostate cancer. Furthermore, we observed five rare, mostly private, missense variants among four genes (BRCA1, BRCA2, PMS2, and ATM) that were predicted to be deleterious and hence likely pathogenic in our patient sample., Conclusions: Protein-truncating mutations in BRCA2 and BRIP1 were discovered in African American men diagnosed with early-onset prostate cancer. Further study is necessary to determine the role of rare, missense variants to prostate cancer incidence, and progression in this group of high-risk men., (© 2018 Wiley Periodicals, Inc.)

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10(-13)). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.

Background: Prostate cancer is the most commonly diagnosed non-skin cancer in men in the United States and the second leading cause of cancer-related mortality. African American men have substantially increased risk of both being diagnosed and dying from the disease. Recent genome-wide genetic association studies have identified a number of common single nucleotide genetic polymorphisms (SNPs) that are associated with prostate cancer in men of European descent. Only a small number of studies have evaluated the association between these genetic variants and prostate cancer in African Americans., Methods: We used logistic regression models to assess the association between prostate cancer in African American men and 24 SNPs from regions previously reported to be associated with prostate cancer in men of European descent., Results: We found nominal evidence (P < 0.05) for association between prostate cancer and three chromosome 8q24 (rs6983561, rs16901979, and rs7000448) and two 10q11 (rs7904463 and rs10740051) SNPs., Conclusions: We confirm recent reports that 8q24 variants identified to be associated with prostate cancer in men of European descent are also associated with prostate cancer in African Americans. Our report is the first to find evidence of association between SNPs near MSMB and prostate cancer in African Americans. Of note, rs7000448 is in strong linkage disequilibrium with rs10761581 in NCOA4, a SNP that has been implicated to be independently associated, with respect to the widely reported SNP rs10993994 in the nearby gene MSMB, with prostate cancer in men of European descent., (Copyright © 2010 Wiley-Liss, Inc.)

Background: Previous studies have found associations between mitochondrial DNA (mtDNA) mutations and several cancer types. Recently, we found that mutations in the mtDNA gene cytochrome c oxidase subunit 1 (COI) were both linked to and associated with prostate cancer (PCa) in Caucasian men. Here we examine the association between COI mutations and PCa in African American men., Methods: The entire COI gene was directly sequenced in 132 PCa cases and 135 controls from the Flint Men's Health Study, a community-based sample of African American men with and without PCa. Associations between all variants and PCa were evaluated., Results: We identified 102 COI single nucleotide polymorphisms (SNPs), including 15 missense variants. Overall, the presence of one or more COI missense variants was not significantly associated with PCa. Individually, two SNPs (T6221C and T7389C) were significantly associated with prostate cancer (P < 0.05) and in strong linkage disequilibrium with each other (r(2) > 0.6)., Conclusions: Of the two significantly associated SNPs, one is a synonymous substitution and the other is part of the African-specific mitochondrial haplogroup (L). Additional research will be needed to determine the clinical relevance of these associations in African populations.

Recent studies have suggested that obesity is associated with lower serum prostate-specific antigen levels, perhaps influencing the recommendation for prostate biopsy and potentially explaining part of the observed poorer prognosis among obese men. African-American men have the greatest rates of prostate cancer and are more likely to die of the disease, making early detection a priority in this group. We present findings from the Flint Men's Health Study, a study of African-American men, that are consistent with most studies suggesting that overweight men have prostate-specific antigen levels that are 0.15 to 0.30 ng/mL lower than those who are not overweight. We have coupled our results with a systematic review of publications in this area.

Background: Association studies have examined the significance of several candidate genes based on biological pathways relevant to prostate carcinogenesis, including both the androgen and insulin-like growth factor pathways. Clinical and epidemiologic evidence suggest that androgens, specifically testosterone and dihydrotestosterone (DHT) are important not only in normal prostate growth but in the pathogenesis of prostate cancer. Similarly, the insulin-like growth factor-1 (IGF-1) signaling pathway regulates both cellular proliferation and apoptosis. Therefore, genes involved in the biosynthesis, activation, metabolism and degradation of androgens and the stimulation of mitogenic and antiapoptotic activities of prostate epithelial cells represent important candidates for affecting the development and progression of prostate cancer., Methods: Using resources from the Flint Men's Health Study, a population-based case control study of African-American men aged 40-79, we evaluated the associations between selected single-nucleotide polymorphisms (SNPs) in the CYP17, CYP3A4, CYP19A1, SDR5A2, IGF1, and IGFBP3 genes and prostate cancer diagnosis in 473 men (131 prostate cancer cases and 342 disease-free controls)., Results: We found a significant association between prostate cancer and selected CYP17 SNP genotypes, with the heterozygous genotype conferring decreased risk. Suggestive evidence for association between IGF1 SNPs and prostate cancer were also found. No significant associations were observed between SNPs in the other genes and prostate cancer., Conclusions: These findings suggest that variation in or around CYP17 and/or IGF1 may be associated with prostate cancer development in the African-American population. Additional studies are needed to determine whether these polymorphisms are indeed associated with prostate cancer risk in African Americans.

Background: Metabolic syndrome refers to a cluster of conditions that includes hypertension, dyslipidemia, central adiposity, and high blood glucose levels. Over the past decade, a growing body of literature suggests that metabolic syndrome may be associated with several different forms of cancer. Because prostate cancer risk is highest among African Americans, and these men, similarly, are more prone to developing specific features of the metabolic syndrome, including hypertension and type-2 diabetes, any relationships would have a significant impact on developing strategies for the primary prevention of prostate cancer., Methods: The Flint Men's Health Study is a community-based, case-control study of prostate cancer conducted exclusively among African Americans. Prostate cancer cases and controls completed an interviewer-administered questionnaire that asked about the respondent's history of high blood pressure and diabetes. All men also participated in a physical examination in which several measures of body composition, including waist circumference, were collected., Results: Hypertension was reported more commonly among men with prostate cancer (cases) compared with men in the control group (odds ratio [OR]. 2.4; 95% confidence interval [95% CI], 1.5-3.7), and cases were more likely to have a waist circumference >102 cm (OR, 1.8; 95% CI, 1.2-2.9). However, self-reported diabetes was not associated with prostate cancer risk. The men with prostate cancer also were more likely than controls to exhibit multiple syndrome characteristics (OR, 1.9; 95% CI, 1.2-3.0)., Conclusions: The current results indicated that features of the metabolic syndrome, specifically abdominal obesity and hypertension, are associated with prostate cancer in African-American men. This relationship, if it is proved causal, suggests that prevention or control of these conditions eventually may lead to a reduction in the incidence of prostate cancer in this high-risk minority group.

Objectives: To explore the familial aggregation of prostate and breast cancer using data from a population-based case-control study of African-American men participating in the Flint Men's Health Study., Methods: A detailed family history questionnaire was administered to 121 African-American men with prostate cancer and 179 African-American male controls. The family history data of prostate and breast cancer in first-degree relatives were compared between men with and without prostate cancer using standard statistical methods., Results: In the Flint Men's Health Study, men with prostate cancer were more likely than controls to report having a brother with prostate cancer (age-adjusted odds ratio 4.80, 95% confidence interval 2.01 to 11.44) or a sister with breast cancer (age-adjusted odds ratio 3.80, 95% confidence interval 1.57 to 9.22)., Conclusions: Although a family history of prostate cancer is a recognized prostate cancer risk factor consistent across different races, few studies have examined the co-clustering of breast and prostate cancer within African-American families. Future studies should focus on racially heterogeneous populations to further explore the observation from the Flint Men's Health Study that having a brother with prostate cancer or a sister with breast cancer may be associated with prostate cancer occurrence. This research may have implications for both gene identification and early detection strategies.

A whole-genome admixture scan in 1,597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer [logarithm of odds (LOD) = 7.1]. The increased risk because of inheriting African ancestry is greater in men diagnosed before 72 years of age (P < 0.00032) and may contribute to the epidemiological observation that the higher risk for prostate cancer in African Americans is greatest in younger men (and attenuates with older age). The same region was recently identified through linkage analysis of prostate cancer, followed by fine-mapping. We strongly replicated this association (P < 4.2 x 10(-9)) but find that the previously described alleles do not explain more than a fraction of the admixture signal. Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it.

Background: Both prostate cancer and diabetes mellitus are common diseases in African-American men. High insulin levels and insulin resistance have been implicated in prostate cancer development, which has prompted a recent investigation of a possible role for germline variation in the insulin gene (INS) and prostate cancer risk., Methods: Four hundred sixty-six African-American men with and without prostate cancer from the Flint Men's Health Study were typed for the INS Pst1 genotype using restriction digest and direct sequencing. An association between the Pst1 genotype and prostate cancer was examined using crude and age-adjusted logistic regression models., Results: African-American men who were homozygous for the INS PstI CC genotype were 1.59 times more likely to be diagnosed with prostate cancer compared to men with the TT or TC genotypes (95% CI = 0.93-2.72). The association appeared stronger among diabetics compared to non-diabetics; however this observation was not statistically significant., Conclusions: Our study, taken together with the report of Ho et al., suggests that the INS Pst1 CC genotype is associated with prostate cancer risk in African-American men. Germline variation in the INS gene should be more fully explored in multiethnic studies to elucidate the molecular variant(s) associated with prostate carcinogenesis.

Objectives: To determine the magnitude of racial disparity in lower urinary tract symptom (LUTS) severity and bother by combining two large comparable epidemiologic studies of community-dwelling white and black men, thereby avoiding many of the referral biases present in previous studies. Prior studies evaluating racial differences in benign prostatic hyperplasia have been hampered by selection bias, because nearly all have used surgical treatment as a marker for benign prostatic hyperplasia., Methods: Data from the Olmsted County Study of Urinary Symptoms and Health Status and the Flint Men's Health Study were combined for a total study sample of 2480 men. We examined LUTS severity and associated bother as measured by the self-administered American Urological Association Symptom Index and Symptom Problem Index., Results: Overall 34% of white men reported moderate/severe LUTS compared with 41% of black men (P <0.001). These patterns were consistent across age and persisted after adjustment for age and other sociodemographic factors. The relationship between LUTS severity and bother differed by race in that black men reported less bother for each unit increase in LUTS (P <0.001)., Conclusions: In contrast to studies based on clinical populations, our community-based study demonstrated greater LUTS severity in black men compared with white men but black men reported less bother for any given level of LUTS severity. Although these findings suggest a racial disparity in benign prostatic hyperplasia, additional studies of anatomic, physiologic, and molecular factors may clarify whether these racial differences are real or due to sociocultural differences in reporting symptom morbidity.

Previous epidemiologic studies evaluating risk factors for lower urinary tract symptoms (LUTS) have focused on White populations. Between September 1996 and January 1998, in a population-based sample of African-American men aged 40-79 years in Flint, Michigan, the authors assessed the role of putative sociodemographic, lifestyle, and medical history risk factors in moderate to severe LUTS, including the subcategories of obstructive and irritative symptoms. After the exclusion of men with prostate cancer or prior prostate surgery and men who were taking alpha-blockers for urinary tract symptoms, 708 participants provided responses to a structured interviewer-administered questionnaire. After multivariable adjustment, current and former smokers were at increased risk of moderate to severe LUTS, including obstructive symptoms. Heavy alcohol consumption and a history of hypertension or diabetes were positively associated with LUTS, and high income (>/=$30,000) was inversely associated with LUTS and with obstructive and irritative symptoms. A history of heart disease was positively associated with LUTS and with irritative symptoms. To the authors' knowledge, this was the first population-based study undertaken in African-American men to evaluate putative risk factors for moderate to severe LUTS, including subcategories of obstructive and irritative urinary symptoms. These results describe associations with specific lifestyle and medical history risk factors.