Affect Prostate Cancer Risk Research Articles

Interaction between Single Nucleotide Polymorphisms in Selenoprotein P and Mitochondrial Superoxide Dismutase Determines Prostate Cancer Risk

Selenium may affect prostate cancer risk via its plasma carrier selenoprotein P which shows dramatically reduced expression in prostate cancer tumors and cell lines. The selenoprotein P (SEPP1) Ala234 single nucleotide polymorphism (SNP) allele is associated with lower plasma selenoprotein P in men, reducing the concentration/activity of other antioxidant selenoproteins. Selenium status also modifies the effect of the mitochondrial superoxide dismutase (SOD2) SNP Ala16Val on prostate cancer risk. We investigated the relationship of these SNPs with prostate cancer risk. DNA from 2,975 cases and 1,896 age-matched controls from the population-based Prostate Cancer in Sweden study were genotyped using TaqMan assays. Cases were designated aggressive or nonaggressive prostate cancers at diagnosis by clinical criteria. Association with prostate cancer was investigated by logistic regression; gene-gene interaction using a general linear model. The mean plasma selenium concentration measured in 169 controls was relatively low (76.0 +/- 17.2 microg/L). SNP genotype distributions were in Hardy-Weinberg equilibrium. SOD2-Ala16+ men were at a greater risk of prostate cancer [odds ratios (OR), 1.19; 95% confidence intervals (CI), 1.03-1.37] compared with SOD2-Val16 homozygotes. Men homozygous for SEPP1-Ala234 who were also SOD2-Ala16+ had a higher risk of prostate cancer (OR, 1.43; 95% CI, 1.17-1.76) and aggressive prostate cancer (OR, 1.60; 95% CI, 1.22-2.09) than those who were SOD2-Val16 homozygotes (interaction, prostate cancer P = 0.05; aggressive prostate cancer P = 0.01). This interaction was stronger in ever-smokers: SOD2-Ala16+ men homozygous for SEPP1-Ala234 had an almost doubled risk of prostate cancer (OR, 1.97; 95% CI, 1.33-2.91; interaction P = 0.001). In a low-selenium population, SOD2-Ala16+ men homozygous for SEPP1-Ala234 are at an increased risk of prostate cancer/aggressive prostate cancer especially if ever-smokers, because they are likely to produce more mitochondrial H(2)O(2) that they cannot remove, thereby promoting prostate tumor cell proliferation and migration.

Common 8q24 Sequence Variations Are Associated with Asian Indian Advanced Prostate Cancer Risk

Three sequence variations (rs1447295, rs16901979, and rs6983267) on 8q24 were recently shown to independently affect prostate cancer risk. Asian Indians have a low prostate cancer risk; however, in the absence of screening practices for the disease, most are diagnosed with metastatic prostate cancer. We evaluated the association of these single nucleotide polymorphisms (SNP) with advanced prostate cancer in 153 prostate cancer cases and 227 age-matched controls (northern India). Overall, there was a positive association between carriers of the allele A of rs1447295 and prostate cancer risk [odds ratio (OR), 1.60; 95% confidence interval (95% CI), 1.01-2.52] but no significant association with carriers of alleles A of rs16901979 and allele G of rs6983267. However, significant associations were observed for both SNPs in men with high Gleason scores (>/=7) and metastasis. Adjusting for age, the ORs were 1.77 (95% CI, 1.05-2.97) for carriers of rs1447295 A and 1.85 (95% CI, 1.04-3.28) for carriers of the rs16901979 A allele. We also observed significant joint effects among these loci associated with prostate cancer risk and severity, suggestive of additive effects of the independent SNPs. The ORs for the combined effects of rs1447295 A with rs16901979 A or rs6983267 G were 2.61 (95% CI, 1.11-6.12) and 1.84 (95% CI, 1.12-3.06), respectively. There was no joint effect between SNPs rs16901979 A and rs6983267 G. These results confirm the significance of these SNPs in prostate cancer etiology in a previously unstudied population who do not undergo prostate cancer screening and are diagnosed with severe disease.

Fatherhood status and prostate cancer risk

Whether fatherhood status affects prostate cancer risk remains controversial. Recently, it was proposed that childless men are at lower prostate cancer risk than men with children and that men with sons may be at lower risk than men with daughters only. National population-based register data were used to address these associations between fatherhood status and prostate cancer risk. The cohort comprised all men born in Denmark between 1935 and 1988, among whom 3400 developed prostate cancer during a total of 51.6 million person-years of follow-up between 1968 and 2003. Childless men were found to be at a 16% reduced risk of prostate cancer compared with fathers (rate ratio [RR] of 0.84; 95% confidence interval [95% CI], 0.73-0.95). The sex of the offspring did not affect prostate cancer risk (fathers with sons vs fathers without sons: RR of 0.99; 95% CI, 0.90-1.08). Among fathers, a significant trend was observed of gradually reduced prostate cancer risk with increasing number of children (P = .009), a pattern applying to both sons (P = .01) and daughters (P = .04). Our national cohort study corroborates the view that men without children constitute a group that is at a moderately reduced risk of prostate cancer. Among men with children, there appears to be a linear decline in prostate cancer risk with increasing number of children that is independent of the sex of the offspring.

Fat and meat intake and prostate cancer risk: The multiethnic cohort study

Dietary fat and meat as potential risk factors for prostate cancer have been the focus of many epidemiologic investigations, and findings from recent studies in particular have been inconsistent. Therefore, we examined the association between these exposures and prostate cancer risk in the Multiethnic Cohort Study. The analyses included 82,483 men in Hawaii and Los Angeles aged >or=45, who completed a detailed quantitative food frequency questionnaire in 1993-1996. During the follow-up period of 8 years, a total of 4,404 incident cases, including 1,278 nonlocalized or high-grade cancer cases, were identified. Cox proportional hazard models were used to estimate relative risks of prostate cancer after adjustment for time on study, ethnicity, family history of prostate cancer, education, body mass index, smoking status and energy intake. Intake of different types of fat (total, saturated, monounsaturated or polyunsaturated), n-6 fatty acid, cholesterol, various meats, and fats from meat showed no association with overall prostate cancer risk or with nonlocalized or high-grade prostate cancer. Furthermore, we found little evidence of any relation of fat and meat intake with prostate cancer risk within any of the 4 racial/ethnic groups (African Americans, Japanese Americans, Latinos and Whites). There was a suggestion of a protective effect of n-3 fatty acid intake that was limited to Latinos and Whites. However, overall, our findings from a large cohort study of ethnically diverse population give no indication that intake of fat and meat substantially affects prostate cancer risk.

Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer

Insulin-like growth factor-I (IGF1) stimulates cell proliferation, decreases apoptosis, and has been implicated in cancer development. Epidemiological studies have shown elevated levels of circulating IGF1 to be associated with increased risk of prostate cancer. To what extent genetic variation in the IGF1 gene is related to prostate cancer risk is largely unknown. We performed a comprehensive haplotype tagging (HT) assessment of single nucleotide polymorphisms (SNPs) representing the common haplotype variation in the IGF1 gene. We genotyped 10 SNPs (9 haplotype tagging SNPs (htSNPs)) within Cancer Prostate in Sweden (CAPS), a case-control study of 2,863 cases and 1,737 controls, in order to investigate if genetic variation in the IGF1 gene is associated with prostate cancer risk. Three haplotype blocks were identified across the IGF1 gene and 9 SNPs were selected as haplotype tagging SNPs. Common haplotypes in the block covering the 3' region of the IGF1 gene showed significant global association with prostate cancer risk (p = 0.004), with one particular haplotype giving an odds ratio of 1.46 (95% CI = 1.15-1.84, p = 0.002). This haplotype had a prevalence of 5% in the study population. Our results indicate that common variation in the IGF1 gene, particularly in the 3' region, may affect prostate cancer risk. Further studies on genetic variations in the IGF1 gene in relation to prostate cancer risk as well as to circulating levels of IGF1 are needed to confirm this novel finding.

Profiling Genetic Variation along the Androgen Biosynthesis and Metabolism Pathways Implicates Several Single Nucleotide Polymorphisms and Their Combinations as Prostate Cancer Risk Factors

Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T(1)-T(2)) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 -34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3 -252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.

Hereditary prostate cancer: clinical aspects.

We review the current epidemiological and genetic knowledge regarding hereditary prostate cancer, and outline its clinical implications. Published articles on hereditary prostate cancer were identified using the MEDLINE data base. A risk of prostate cancer, particularly early onset disease, is strongly affected by family history (number of relatives with prostate cancer and their age at diagnosis). A family history of prostate cancer increases the positive predictive value of prostate specific antigen testing and, hence, heredity should always be assessed when deciding whether to perform biopsies in a man with a prostate specific antigen level of 3 to 10 ng./ml. Epidemiological studies indicate that dominantly inherited susceptibility genes with high penetrance cause 5% to 10% of all prostate cancer cases, and as much as 30% to 40% of early onset disease. More than a half dozen chromosome loci that may comprise such genes have been mapped, but as of May 2002 no prostate cancer susceptibility gene of major importance had been cloned. Most likely, environmental factors and comparatively common variants of several other genes affect prostate cancer risk in families with or without multiple cases of the disease. On average, hereditary prostate cancer is diagnosed 6 to 7 years earlier than sporadic prostate cancer, but does not otherwise differ clinically from the sporadic form. As a consequence of the earlier onset, a greater proportion of men with hereditary prostate cancer die of the disease than those with nonhereditary prostate cancer. At present, the only clinically applicable measure to reduce prostate cancer mortality in families with hereditary disease is screening, with the aim of diagnosing the disease when it is still in a curable stage. Hereditary susceptibility is now considered the strongest risk factor for prostate cancer and has profound clinical importance. The genetic mechanism behind such susceptibility has turned out to be more complex than initially thought, and will probably not be completely understood for many years to come.

Alcohol consumption and risk of prostate cancer in middle-aged men.

Alcohol consumption is a modifiable lifestyle factor that may affect prostate cancer risk. Alcohol alters the hormonal milieu and contains chemical substances such as flavonoids (red wine), which may alter tumor cell growth. Data from a population-based case-control study in King County, WA, were utilized to evaluate the association of alcohol consumption with prostate cancer in middle-aged men. A total of 753 newly diagnosed prostate cancer cases, 40-64 years of age, participated in the study. Seven hundred three control subjects, frequency matched to cases by age, were selected through random digit dialing. All participants completed an in-person interview on lifetime alcohol consumption and other risk factors for prostate cancer. Logistic regression models were used to estimate odds ratios (OR) and assess significance (95% confidence intervals [CI]). All tests of statistical significance were two-sided. No clear association with prostate cancer risk was seen for overall alcohol consumption. Each additional glass of red wine consumed per week showed a statistically significant 6% decrease in relative risk (OR = 0.94; 95% CI = 0.90-0.98), and there was evidence for a decline in risk estimates across increasing categories of red wine intake (trend p = 0.02). No clear associations were seen for consumption of beer or liquor. Our present study suggests that consumption of beer or liquor is not associated with prostate cancer. There may be, however, a reduced relative risk associated with increasing level of red wine consumption. Further research is needed to evaluate the potential negative association between red wine intake and prostate cancer risk.

Dietary intake of n−3 and n−6 fatty acids and the risk of prostate cancer

Laboratory studies have shown that n-3 fatty acids inhibit and n-6 fatty acids stimulate prostate tumor growth, but whether the dietary intake of these fatty acids affects prostate cancer risk in humans remains unclear. We prospectively evaluated the association between intakes of alpha-linolenic (ALA; 18:3n-3), eicosapentaenoic (EPA; 20:5n-3), docosahexaenoic (DHA; 22:6n-3), linoleic (LA; 18:2n-6), and arachidonic (AA; 20:4n-6) acids and prostate cancer risk. A cohort of 47 866 US men aged 40-75 y with no cancer history in 1986 was followed for 14 y. During follow-up, 2965 new cases of total prostate cancer were ascertained, 448 of which were advanced prostate cancer. ALA intake was unrelated to the risk of total prostate cancer. In contrast, the multivariate relative risks (RRs) of advanced prostate cancer from comparisons of extreme quintiles of ALA from nonanimal sources and ALA from meat and dairy sources were 2.02 (95% CI: 1.35, 3.03) and 1.53 (0.88, 2.66), respectively. EPA and DHA intakes were related to lower prostate cancer risk. The multivariate RRs of total and advanced prostate cancer from comparisons of extreme quintiles of the combination of EPA and DHA were 0.89 (0.77, 1.04) and 0.74 (0.49, 1.08), respectively. LA and AA intakes were unrelated to the risk of prostate cancer. The multivariate RR of advanced prostate cancer from a comparison of extreme quintiles of the ratio of LA to ALA was 0.62 (0.45, 0.86). Increased dietary intakes of ALA may increase the risk of advanced prostate cancer. In contrast, EPA and DHA intakes may reduce the risk of total and advanced prostate cancer.