ICAM gene cluster SNPs and prostate cancer risk in African Americans

Intercellular adhesion molecules (ICAMs) are known to be involved in various human cancers. An ICAM gene cluster lying within a 26 kb region on chromosome 19p13.2, and containing ICAM1, ICAM4, and ICAM5 has recently been identified as harboring a breast and prostate cancer susceptibility locus in two populations of European ancestry from Germany and Australia. The objective of this study was to confirm the ICAM association with prostate cancer in a sample of African American prostate cancer cases (N = 286) and controls (N = 391). Six single nucleotide polymorphisms (SNPs) within the three ICAM genes were genotyped. To control for potential population stratification an ancestry-adjusted association analysis was performed. We found that ICAM1 SNPs, −9A/C (rs5490) and K469E (rs5498) were associated with prostate cancer risk in men with a family history of prostate cancer (P = 0.008). Specifically, increased risk was observed for individuals who possessed the CC genotype of the −9 A/C variant (odds ratio = 2.5; 95% CI = 1.0–6.3) and at least one G allele of non-synonymous K469E variant (odds ratio = 1.8; 95% CI = 1.2–3.1). Strong linkage disequilibrium was observed across the ICAM region (P < 0.001). A common haplotype within the ICAM gene cluster, harboring the −9A/C variant was significantly associated with prostate cancer (P = 0.03), mainly due to men with family history (P = 0.01). Our results replicate previous findings of association of the ICAM gene cluster with prostate cancer and suggest that common genetic variation within ICAM1 and not ICAM5 may be an important risk factor for prostate cancer.     

Association of SULT2A1 allelic variants with plasma adrenal androgens and prostate cancer in African American men

Dehydroepiandrosterone (DHEA) sulfate which is present at micromolar levels in the plasma, can be desulfated to supply free DHEA for metabolism to androgens or estrogens in peripheral tissues. Human cytosolic sulfotransferase (SULT) 2A1 catalyzes DHEA sulfation in the adrenal cortex. Three SULT2A1 nonsynonymous coding single nucleotide polymorphisms (SNPs), identified only in African Americans (AA), are associated with decreased levels of activity and expression as compared to wild-type cDNA when expressed in COS cells. To test whether the SNPs are associated with decreased plasma androgens, 124 normal AA men were genotyped and plasma DHEA, DHEA-sulfate and testosterone levels determined. The two SNPs identified in these participants occurred at allelic frequencies of 0.044 (G187C) and 0.101 (G781A). The G187C SNP was highly linked to the G781A SNP. Although no differences in hormone levels were associated with the individual SNPs, a significant increase in the DHEA:DHEA-sulfate ratio was observed in participants with a heterozygous G187C/G781A genotype. Increased free DHEA levels may result in increased testosterone synthesis and stimulation in the prostate, therefore a group of AA prostate cancer (PC) patients and controls were genotyped. No significant association of the presence of the different SULT2A1 alleles with the occurrence of PC was detected.     

A genome-wide association study of prostate cancer in West African men

Age-adjusted mortality rates for prostate cancer are higher for African-American men compared with those of European ancestry. Recent data suggest that West African men also have elevated risk for prostate cancer relative to European men. Genetic susceptibility to prostate cancer could account for part of this difference. We conducted a genome-wide association study (GWAS) of prostate cancer in West African men in the Ghana Prostate Study. Association testing was performed using multivariable logistic regression adjusted for age and genetic ancestry for 474 prostate cancer cases and 458 population-based controls on the Illumina HumanOmni-5 Quad BeadChip. The most promising association was at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3 (p = 1.29E?7). In sub-analyses, SNPs at 5q31.3 were associated with high Gleason score (≥7) cancers, the strongest of which was a missense SNP in PCDHA1 (rs34575154, p = 3.66E?8), and SNPs at Xq28 (rs985081, p = 8.66E?9) and 6q21 (rs2185710, p = 5.95E?8) were associated with low Gleason score (<7) cancers. We sought to validate our findings in silico in the African Ancestry Prostate Cancer GWAS Consortium, but only one SNP, at 10p14, replicated at p < 0.05. Of the 90 prostate cancer loci reported from studies of men of European, Asian or African-American ancestry, we were able to test 81 in the Ghana Prostate Study, and 10 of these replicated at p < 0.05. Further genetic studies of prostate cancer in West African men are needed to confirm our promising susceptibility loci.     

African American-preponderant single nucleotide polymorphisms (SNPs) and risk of breast cancer

Background: African American women more often present with more aggressive types of breast cancer than Caucasian women, but little is known whether genetic polymorphisms specific to or disproportionate in African Americans are associated with their risk of breast cancer. Methods: A population-based case-control study was conducted including 194 cases identified through the Metropolitan Detroit Cancer Surveillance System and 189 controls recruited through random digit dialing to examine polymorphisms in genes involved in estrogen metabolism and action. Results: The African American-specific CYP1A1 5639C allele was associated with an increased risk of breast cancer (odds ratio (OR) = 2.34, 95% confidence interval (CI) 1.23–4.44) and this association with the CYP1A1 5639 locus was dependent on another polymorphism in the CYP3A4 gene (P = 0.043 for the interaction). In addition, African American-predominant CYP1B1 432 Val allele was significantly more often found in the cases than in the controls overall and the HSD17B1 312 Gly allele was specifically associated with premenopausal breast cancer risk (OR = 3.00, 95%CI 1.29–6.99). Conclusion: These observations need to be confirmed in larger studies due to the limited statistical power of the study based on a small number of cases.     

Vitamin D receptor polymorphisms and prostate cancer risk in Brazilian men

Vitamin D seems to be an important determinant of prostate cancer risk and inherited polymorphisms in the 3'untranslated region of the vitamin D receptor (VDR) gene have been associated with the risk and progression of prostate cancer in some populations. We therefore studied VDR gene polymorphisms, as detected by Apal and Taql restriction fragments, in multiethnic Brazilian men (165 patients and 200 controls) for association with prostate cancer risk and parameters of disease severity (serum PSA, Gleason score and tumor stage). No statistical correlations were found. The unique ethnical background of Brazilian subjects, characterized by an extensive racial mixture of European, African-American and Native American, might have blunted any ethnic-specific significance of VDR polymorphisms. Further investigations of the associations between VDR and other genetic or environmental factors are warranted.     

Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans

GWAS of prostate cancer have been remarkably successful in revealing common genetic variants and novel biological pathways that are linked with its etiology. A more complete understanding of inherited susceptibility to prostate cancer in the general population will come from continuing such discovery efforts and from testing known risk alleles in diverse racial and ethnic groups. In this large study of prostate cancer in African American men (3,425 prostate cancer cases and 3,290 controls), we tested 49 risk variants located in 28 genomic regions identified through GWAS in men of European and Asian descent, and we replicated associations (at p≤0.05) with roughly half of these markers. Through fine-mapping, we identified nearby markers in many regions that better define associations in African Americans. At 8q24, we found 9 variants (p≤6×10⁻⁴) that best capture risk of prostate cancer in African Americans, many of which are more common in men of African than European descent. The markers found to be associated with risk at each locus improved risk modeling in African Americans (per allele OR = 1.17) over the alleles reported in the original GWAS (OR = 1.08). In summary, in this detailed analysis of the prostate cancer risk loci reported from GWAS, we have validated and improved upon markers of risk in some regions that better define the association with prostate cancer in African Americans. Our findings with variants at 8q24 also reinforce the importance of this region as a major risk locus for prostate cancer in men of African ancestry.     

DNA methylation profiles in African American prostate cancer patients in relation to disease progression

This study examined whether differential DNA methylation is associated with clinical features of more aggressive disease at diagnosis and prostate cancer recurrence in African American men, who are more likely to die from prostate cancer than other populations. Tumor tissues from 76 African Americans diagnosed with prostate cancer who had radical prostatectomy as their primary treatment were profiled for epigenome-wide DNA methylation levels. Long-term follow-up identified 19 patients with prostate cancer recurrence. Twenty-three CpGs were differentially methylated (FDR q ≤ 0.25, mean methylation difference ≥ 0.10) in patients with vs. without recurrence, including CpGs in GCK, CDKL2, PRDM13, and ZFR2. Methylation differences were also observed between men with metastatic-lethal prostate cancer vs. no recurrence (five CpGs), regional vs. local pathological stage (two CpGs), and higher vs. lower tumor aggressiveness (one CpG). These results indicate that differentially methylated CpG sites identified in tumor tissues of African American men may contribute to prostate cancer aggressiveness.     

ELAC2 and prostate cancer risk in Afro-Caribbeans of Tobago

To test the hypothesis that variation in the putative prostate cancer susceptibility gene ELAC2 contributes to the elevated risk of prostate cancer in Afro-Caribbean males from Tobago, we genotyped the S217L and A514T polymorphisms, previously reported to be associated with prostate cancer risk in a large sample of cases and controls. The frequency of the high-risk Leu allele at the S217L site was the same in cases and controls. Both cases and controls were homozygous for the low-risk Ala allele at the A514T site. In addition, we sequenced the exons and 3'- and 5'-flanking regions of ELAC2 in 24 individuals with histologically confirmed prostate cancer. We identified 17 new single nucleotide polymorphisms. An A(-1196)T polymorphism, which alters a predicted TATA box consensus sequence, was tested in cases and controls, and no significant difference in allele or genotype frequencies was observed. The absence of ELAC2 mutations and lack of association between polymorphisms in ELAC2 and prostate cancer in cases and controls leads us to conclude that ELAC2 does not contribute significantly to the elevated prevalence of prostate cancer in Afro-Caribbean males of Tobago.     

Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk

Androgen receptor (AR) has long been hypothesized to play an important role in prostate cancer etiology. Two trinucleotide repeat polymorphisms (CAG and GGC repeats in exon 1 of the AR gene) have been investigated as risk factors for prostate cancer in several studies. However, the results are inconclusive, probably because of the variations of study designs, characteristics of study samples, and choices of analytical methods. In this study, we evaluated evidence for linkage and association between the two AR repeats and prostate cancer by using the following comprehensive approaches: (1) a combination of linkage and association studies, (2) a test for linkage by parametric analysis and the male-limited X-linked transmission/disequilibrium test (XLRC-TDT), (3) a test for association by using both population-based and family-based tests, and (4) a study of both hereditary and sporadic cases. A positive but weak linkage score (HLOD=0.49, P=0.12) was identified in the AR region by parametric analysis; however, stronger evidence for linkage in the region, especially at the GGC locus, was observed in the subset of families whose proband had < or = 16 GGC repeats (HLOD=0.70, P=0.07) or by using XLRC-TDT ( z'=2.65, P=0.008). Significantly increased frequencies of the < or = 16 GGC repeat alleles in 159 independent hereditary cases (71%) and 245 sporadic cases (68%) cases compared with 211 controls (59%) suggested that GGC repeats were associated with prostate cancer ( P=0.02). Evidence for the association between the < or = 16 GGC repeats and prostate cancer risk was stronger with XLRC-TDT ( z'=2.66, P=0.007). No evidence for association between the CAG repeats and prostate cancer risk was observed. The consistent results from both linkage and association studies strongly implicate the GGC repeats in the AR as a prostate cancer susceptibility gene. Further studies on this polymorphism in other independent data sets and functional analysis of the GGC repeat length on AR activity are warranted.     

Occupational exposure to solar ultraviolet B radiation and risk of prostate cancer in Danish men

ObjectivesFormer epidemiological studies have indicated that solar ultraviolet B radiation (UV) may reduce the risk of prostate cancer, however, the evidence is inconclusive. To contribute with evidence, the present study aimed to evaluate the association between occupational UV exposure and prostate cancer in Danish men.MethodsA total of 12,268 men diagnosed with primary prostate cancer before age 70 were identified via the Danish Cancer Registry. The Danish Civil Registration System was used to randomly select five male controls matched on year of birth, alive and free of prostate cancer at the time of diagnosis of the index case. Full individual-level employment history was retrieved from the Danish Supplementary Pension Fund Register and linked to a job exposure matrix to assess occupational UV exposure. Conditional logistic regression was used to estimate odds ratios (ORs) with corresponding 95 % confidence intervals.ResultsWe observed an inverse association between ever exposure to occupational UV and prostate cancer (OR=0.93, 95 % CI: 0.89–0.97). Longer duration of exposure (≥20 years: OR=0.90, 95 % CI: 0.84–0.96) and highest cumulative exposure (OR=0.90, 95 % CI: 0.84–0.96) were both inversely associated with disease risk.ConclusionsThe present study indicates a modest protective effect from occupational UV exposure on the risk of prostate cancer. This finding needs further attention in future large-scale studies.     

Carotid baroreflex responsiveness is impaired in normotensive African American men

There are important differences in autonomic function and cardiovascular responsiveness between African Americans (AA) and Caucasian Americans (CA). This study tested the hypothesis that carotid baroreflex (CBR) responsiveness is impaired in normotensive AA compared with normotensive CA at rest. CBR control of heart rate (HR) and mean arterial blood pressure (MAP) was assessed in 30 nonhypertensive male subjects (15 AA; 15 CA; age 18-33 yr) with 5-s periods of neck pressure (NP; simulated hypotension) and neck suction (NS; simulated hypertension) ranging from +45 to -80 Torr during rest. Carotid-cardiac stimulus-response curves revealed a significantly lower minimum HR response in the CA compared with AA (40.8 ± 2.4 vs. 49.8 ± 2.9 beats/min, respectively; P < 0.05). In addition, the magnitude of the mean HR response to all trials of NS (-20, -40, -60, and -80 Torr) was attenuated in the AA group (AA, -10.1 ± 1.7 vs. CA, -14.9 ± 2.2 beats/min; P < 0.05), while no significant differences were found in the magnitude of the mean HR response to NP (+15, +30, and +45 Torr) between racial groups. There were no significant differences in the carotid-vasomotor stimulus-response curves between racial groups. Also, while no racial differences were found in the magnitude of the mean MAP response to all trials of NS, the magnitude of the mean MAP response to all trials of NP was attenuated in the AA group (AA, 7.2 ± 1.3 vs. CA, 9.3 ± 1.1 mmHg; P < 0.05). Together, these findings support inherent differences in short-term blood pressure regulation between racial groups that exhibit different relative risk for the development of hypertension.     

Analysis of the RNASEL gene in familial and sporadic prostate cancer

The RNASEL gene on chromosome 1q25 was recently identified as a candidate gene for hereditary prostate cancer (PC). To confirm these findings, we screened 326 patients from 163 families with familial PC for potential germline mutations, by use of conformation-sensitive gel electrophoresis, followed by direct sequence analysis. A total of six variants were identified, including one intronic and five exonic changes (three missense and two silent alterations). There were no unequivocal pathogenic changes. To further test for potential associations between genes and increased risk for disease, the three missense polymorphisms (Ile97Leu, Arg462Gln, and Glu541Asp) were genotyped in 438 patients with familial PC and in 510 population-based control subjects. Association testing revealed no significant differences between patients and control subjects for either the Leu97 variant (chi(2) trend test = 1.42; P=.23) or the Asp541 variant (chi2=1.52; P=.22). However, significant differences were detected for the Arg462Gln genotypes (chi2=5.20; P=.02; odds ratio [OR] = 0.54; 95% confidence interval [CI] 0.32-0.91) when the genotype Gln/Gln was compared with Arg/Arg. In subset analyses, associations were also observed in the younger group (age at diagnosis 相似文献   

MicroRNAs that affect prostate cancer: emphasis on prostate cancer in African Americans

Abstract

Although concerted efforts have been directed toward eradicating health disparities in the United States, the disease and mortality rates for African American men still are among the highest in the world. We focus here on the role of microRNAs (miRNAs) in the signaling pathways of androgen receptors and growth factors that promote the progression of prostate cancer to more aggressive disease. We explore also how differential expression of miRNAs contributes to aggressive prostate cancer including that of African Americans.     

Association of genetic and non-genetic risk factors with the development of prostate cancer in Malaysian men

There is growing global interest to stratify men into different levels of risk to developing prostate cancer, thus it is important to identify common genetic variants that confer the risk. Although many studies have identified more than a dozen common genetic variants which are highly associated with prostate cancer, none have been done in Malaysian population. To determine the association of such variants in Malaysian men with prostate cancer, we evaluated a panel of 768 SNPs found previously associated with various cancers which also included the prostate specific SNPs in a population based case control study (51 case subjects with prostate cancer and 51 control subjects) in Malaysian men of Malay, Chinese and Indian ethnicity. We identified 21 SNPs significantly associated with prostate cancer. Among these, 12 SNPs were strongly associated with increased risk of prostate cancer while remaining nine SNPs were associated with reduced risk. However, data analysis based on ethnic stratification led to only five SNPs in Malays and 3 SNPs in Chinese which remained significant. This could be due to small sample size in each ethnic group. Significant non-genetic risk factors were also identified for their association with prostate cancer. Our study is the first to investigate the involvement of multiple variants towards susceptibility for PC in Malaysian men using genotyping approach. Identified SNPs and non-genetic risk factors have a significant association with prostate cancer.     

RNASEL 1623A>C variant is associated with the risk of prostate cancer in African descendants

Association between ribonuclease L (RNASEL) gene 1623A>C polymorphism and prostate cancer (PCa) susceptibility has been assessed in large quantities of studies but with controversial conclusions. We undertook a pooled analysis containing 7397 PCa cases and 6088 control subjects to assess the correlation between RNASEL 1623A>C polymorphism and PCa risk. Moreover, we used enzyme-linked immunosorbent assay to test the serum RNASEL expression among patients enrolled in our centers and in-silico tools were also utilized. The overall results of our analysis indicated a positive relationship between 1623A>C variant and PCa risk (allelic contrast, odds ratio [OR] = 1.07; 95% confidence interval [CI] = 1.02-1.12; P_{heterogeneity} = 0.575; CC vs AA, OR = 1.14; 95% CI = 1.03-1.26; P_{heterogeneity} = 0.217; CC + CA vs AA, OR = 1.10; 95% CI = 1.01-1.19; P_{heterogeneity} = 0.303; and CC vs CA + AA, OR = 1.08; 95% CI = 1.00-1.17; P_{heterogeneity} = 0.298). In ethnicity subgroup analysis, similar results were especially indicated in African descendants. In addition, serum RNASEL levels in PCa cases with CC + CA genotypes were higher than those with AA genotypes. Our present study showed evidence that RNASEL 1623A>C polymorphism is related to PCa risk, especially in African descendants.