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.     

Two common chromosome 8q24 variants are associated with increased risk for prostate cancer

Two variants (rs1447295/DG8S737) of chromosome 8q24 were recently reported to be associated with increased risk of prostate cancer (PC). To confirm this finding, we genotyped and compared the frequencies of these polymorphisms among 1,121 Caucasian men with PC (435 men with familial PC, 491 men with sporadic PC, and 195 men with aggressive PC) to 545 population-based controls. For the single nucleotide polymorphism marker rs1447295, frequencies of the minor allele (A) were 10.3% in controls, 11.9% in sporadic cases, 16.7% in familial cases, and 17.2% in aggressive cases. Compared with controls, the A allele was significantly more common in both familial PC [odds ratios (OR), 1.93; 95% confidence intervals (95% CI), 1.37-2.72; P = 0.0004] and aggressive PC (OR, 1.87; 95% CI, 1.28-2.74; P = 0.0005) but not for sporadic PC (OR, 1.16; 95% CI, 0.85-1.58; P = 0.25). Although the A allele was more frequent in aggressive PC cases when compared with controls, the allele frequencies were similar among cases with high- and low-grade PC (Gleason grades <7 and >/=7, respectively). For the microsatellite marker DG8S737, the -8 allele was significantly more frequent in familial PC (OR, 1.68; 95% CI, 1.09-2.60; P = 0.031), whereas the -10 allele was more frequent in aggressive PC (OR, 2.85; 95% CI, 1.52-5.36; P = 0.0004). Haplotype analysis showed significant differences in haplotype frequencies between the familial PC (P = 0.006) and aggressive PC (P = 0.005) cases versus controls. The -8/A haplotype showed the strongest association with familial PC (P = 0.008), whereas the -10/A haplotype was most strongly associated with aggressive PC (P = 0.00005). These results further confirm the importance of these two polymorphic variants (rs1447295 and DG8S737) as risk factors for PC. However, the mechanism explaining this increased risk has not yet been established.     

Confirmation of a positive association between prostate cancer risk and a locus at chromosome 8q24.

BACKGROUND: Family-based linkage studies, association studies, and studies of tumors have highlighted human chromosome 8q as a genomic region of interest for prostate cancer susceptibility loci. Recently, a locus at 8q24, characterized by both a single nucleotide polymorphism (SNP) and a microsatellite marker, was shown to be associated with prostate cancer risk in Icelandic, Swedish, and U.S. samples. Although the data were provocative, the U.S. samples were not population based, which precludes assessment of the potential contribution of this locus to prostate cancer incidence in the United States. METHODS: We analyzed both markers in a population-based, case-control study of middle-aged men from King County, Washington. RESULTS: Overall, there was a significant positive association between the A allele of the SNP rs1447295 and prostate cancer risk [odds ratio, 1.4; 95% confidence interval (95% CI), 1.1-2.0] but no significant association with the microsatellite DG8S737. However, significant associations were observed for both markers in men with high Gleason scores. Adjusting for age, first-degree family history of prostate cancer, and prostate cancer screening history, the adjusted odds ratios were 1.4 (95% CI, 1.1-1.8) for the A allele of the SNP and 1.9 (95% CI, 1.2-2.8) for the -10 allele of the microsatellite. CONCLUSIONS: These data suggest that the locus on chromosome 8q24 harbors a genetic variant associated with prostate cancer and that the microsatellite marker is a stronger risk factor for aggressive prostate cancers defined by poorly differentiated tumor morphology.     

A common 8q24 variant in prostate and breast cancer from a large nested case-control study

Two recent studies independently identified polymorphisms in the 8q24 region, including a single nucleotide polymorphism (rs1447295), strongly associated with prostate cancer risk. Here, we replicate the overall association in a large nested case-control study from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium using 6,637 prostate cancer cases and 7,361 matched controls. We also examine whether this polymorphism is associated with breast cancer among 2,604 Caucasian breast cancer cases and 3,118 matched controls. The rs1447295 marker was strongly associated with prostate cancer among Caucasians (P = 1.23 x 10(-13)). When we exclude the Multiethnic Cohort samples, previously reported by Freedman et al., the association remains highly significant (P = 8.64 x 10(-13)). Compared with wild-type homozygotes, carriers with one copy of the minor allele had an OR(AC) = 1.34 (99% confidence intervals, 1.19-1.50) and carriers with two copies of the minor allele had an OR(AA) = 1.86 (99% confidence intervals, 1.30-2.67). Among African Americans, the genotype association was statistically significant in men diagnosed with prostate cancer at an early age (P = 0.011) and nonsignificant for those diagnosed at a later age (P = 0.924). This difference in risk by age at diagnosis was not present among Caucasians. We found no statistically significant difference in risk when tumors were classified by Gleason score, stage, or mortality. We found no association between rs1447295 and breast cancer risk (P = 0.590). Although the gene responsible has yet to be identified, the validation of this marker in this large sample of prostate cancer cases leaves little room for the possibility of a false-positive result.     

Variants on ESR1 and their Association with Prostate Cancer Risk: A Meta-analysis

Background: Epidemiological studies evaluating the association of two variants rs9340799 and rs2234693 onestrogen receptor 1 (ESR1) with prostate risk have generated inconsistent results. Methods: A meta-analysis washere conducted to systematically evaluate the relationship of these two variants with prostate cancer susceptibility.Results: For rs9340799, heterozygosity of T/C carriers showed a significant increased prostate cancer risk with apooled odds ratio (OR) of 1.34 (95% CI = 1.06-1.69) while homozygote C/C carriers showed an increased but notstatistically significant association with prostate cancer risk (pooled OR = 1.29, 95% CI = 0.94-1.79). Comparedto the homozygous TT carriers, the allele C carriers showed a 31% increased risk for prostate cancer (pooledOR = 1.31, 95% CI = 1.06-1.63). No significant association between the rs2234693 and prostate cancer riskwas found with the pooled OR of 1.15 (95% CI = 0.97-1.39, T/C and C/C vs. T/T) under the dominant geneticmodel. Compared to the homozygote T/T carriers, the heterozygous T/C carriers did not show any significantlydifferent risk of prostate cancer (pooled OR = 1.13, 95% CI = 0.94-1.36) and the homozygous C/C carriers alsodid not show a significant change for prostate cancer risk compared to the wide-type T/T carriers (pooled OR= 1.26, 95% CI = 0.98-1.62). Conclusions: These data suggested that variant rs9340799, but not rs2234693, onESR1 confers an elevated risk of prostate cancer.     

Association of 8 Loci on Chromosome 8q24 with Prostate Carcinoma Risk in Northern Chinese Men

Multiple genetic studies have confirmed association of 8q24 variants with susceptibility to prostate cancer(PCa). As PCa risk SNPs may also influence disease outcome, we studied here eight 8q24 risk alleles, andevaluated their role in PCa clinical covariates in northern Chinese men. Blood samples and clinical informationwere collected from ethnically Chinese men from Northern China with histologically-confirmed PCa (n=289)and from age-matched normal controls (n=288). Eight 8q24 SNPs were genotyped by polymerase chain reactionhigh-resolution melting analysis in 577 subjects. We examined the prevalence distribution of 8q24 risk alleles andanalyzed the associations between the risk allele and PCa and clinical covariates to infer their impact on aggressivePCa. Three of the eight SNPs were associated with PCa risk in northern Chinese men, including rs16901966 (OR1.31, 95% CI 1.01-1.70, p=0.042), rs1447295 (OR 1.47, 95% CI 1.09-1.98, p=0.011) and rs10090154 (OR 1.55, 95%CI 1.14-2.12, p=0.005). Haplotype analysis based association with the risk alleles revealed significant differencesbetween cases and controls (OR 1.43, 95%CI 0.99-2.06, p=0.049). The risk alleles rs16901966, rs1447295 andrs10090154 were associated with age at diagnosis and tumor stage as compared with controls, while rs16901966was associated with aggressive PCa (OR 1.43, 95% CI 1.01-2.03, p=0.042). The evidence for 8q24 SNPs with PCarisk in northern Chinese men showed rs16901966, rs1447295 and rs10090154 at 8q24 (region 1, region 2) to bestrongly associated with PCa and clinical covariates. The three SNPs at 8q24 could be PCa susceptible geneticmarkers in northern Chinese men.     

Vitamin D receptor genotypes/haplotypes and prostate cancer risk.

The vitamin D receptor (VDR) gene has been associated with prostate cancer, although previous results are somewhat equivocal. To further study this, we did a family-based case-control study (N = 918) of the association between prostate cancer and six common VDR variants: Cdx2, FokI, BsmI, ApaI, TaqI, and the poly-A microsatellite. Looking at each variant alone, only FokI and ApaI were associated with disease. The FokI FF genotype was inversely associated with prostate cancer among men with less advanced disease (i.e., Gleason score <7 and tumor stage 相似文献   

Metallothionein 2A genetic polymorphisms and risk of prostate cancer in a Polish population

Metallothionein 2A (MT2A) is the most expressed metallothionein (MT) isoform in prostate cells. A number of studies have demonstrated altered MT2A expression in various human tumors, including prostate cancer. We conducted an association study to examine whether MT2A gene polymorphisms are associated with a risk of prostate cancer. Genotyping was conducted using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Three single nucleotide polymorphisms (SNPs), rs28366003, rs1610216, and rs10636, were genotyped in 358 prostate cancer cases and 406 population controls. One SNP in MT2A (rs28366003) showed a positive association with prostate cancer. Compared to homozygous common allele carriers, heterozygosity for the G variant (odds ratio (OR)=2.30, 95% confidence interval (CI): 1.50-3.47, P-trend<0.0001; the OR assuming a dominant model 2.43 (95% CI: 1.62-3.61, P(dominant)=0.001) after adjustment for age) had a significantly increased risk of prostate cancer in a Polish population. Our data suggest that the rs28366003 SNP in MT2A is associated with the risk of prostate cancer in a Polish population.     

Association of genetic variants at 8q24 with breast cancer risk.

Recent whole genome association studies of prostate, breast, and colorectal cancer have identified susceptibility loci on 8q24. We genotyped three variants associated with prostate cancer (rs10090154, rs13254738, and rs7000448), one associated with both prostate and colorectal cancer (rs6983267), and one associated with breast cancer (rs13281615) in a series of 1,499 breast cancer cases and 1,390 controls. 1,267 (85%) of the cases had two primary breast cancers. Our analysis provides further evidence of the relationship between rs13281615 and risk of breast cancer, with heterozygote odds ratio (OR) 1.30 95% confidence interval (CI) 1.09-1.54 and homozygote OR 1.52 (95% CI, 1.22-1.89; P trend = 0.00003), and confirms the prediction that the risk is substantially higher in this genetically enriched series (OR per allele, 1.24; 95% CI, 1.12-1.38) than in a large series of mainly unselected cases (reported OR per allele, 1.08; 95% CI, 1.05-1.11). We observed a protective effect of rs13254738 for breast cancer (allelic OR, 0.88; 95% CI, 0.78-0.98; P = 0.02), which is supported by the Cancer Genetic Markers of Susceptibility data (pooled allelic OR, 0.88; 95% CI, 0.81-0.96; P = 0.003). None of the other three single nucleotide polymorphisms, two associated with prostate (rs10090154 and rs7000448) and one with both prostate and colorectal cancers (rs6583267), was associated with breast cancer risk in our study. This evidence of a protective effect for breast cancer of one variant (rs13254738) that has been associated previously with a 1.25-fold increased risk of prostate cancer, with no effect for the two other variants, indicates that the effects of the risk alleles clustered at 8q24 are cancer site specific.     

Polymorphisms in polycyclic aromatic hydrocarbon metabolism and conjugation genes, interactions with smoking and prostate cancer risk.

The relationship between cigarette smoking and prostate cancer remains unclear. Any potential association may depend on the individuals' ability to metabolize and detoxify cigarette carcinogens--such as polycyclic aromatic hydrocarbons. To investigate this, we studied the association between prostate cancer and smoking, as well as the main and modifying effects of functional polymorphisms in genes that metabolize polycyclic aromatic hydrocarbons (CYP1A1 Ile(462)Val, microsomal epoxide hydrolase His(139)Arg) and detoxify reactive derivatives (GSTM1 null deletion, GSTT1 null deletion, GSTP1 Ile(105)Val and Ala(114)Val) using a family-based case-control design (439 prostate cancer cases and 479 brother controls). Within the entire study population, there were no main effects for smoking or any of the polymorphisms. However, the nondeleted GSTM1 allele was inversely associated with prostate cancer [odds ratio (OR), 0.50; 95% confidence interval (95% CI), 0.26-0.94] among men with less aggressive disease (Gleason score < 7 and clinical tumor stage < T2c) and positively associated (OR, 1.68; 95% CI, 1.01-2.79) with prostate cancer in men with more aggressive disease (Gleason score > or = 7 or clinical tumor stage > or = T2c). We also found a statistically significant negative multiplicative interaction between the GSTM1 nondeleted allele and heavy smoking (> 20 pack-years) in the total study population (P = 0.01) and in Caucasians (P = 0.01). Among Caucasians, heavy smoking increased prostate cancer risk nearly 2-fold in those with the GSTM1 null genotype (OR, 1.73; 95% CI, 0.99-3.05) but this increased risk was not observed in heavy smokers who carried the GSTM1 nondeleted allele (OR, 0.95; 95% CI, 0.53-1.71). Our results highlight the importance of considering genetic modifiers of carcinogens when evaluating smoking in prostate cancer.     

Effect of genetic variability within 8q24 on aggressiveness patterns at diagnosis and familial status of prostate cancer

PURPOSE: Recently, two independent loci located at 8q24 that contribute to prostate cancer risk in men of European origin were identified. EXPERIMENTAL DESIGN: Using Bayesian probability network and logistic regression model, we searched for associations between 34 single-nucleotide polymorphisms (SNP) located at 8q24 and the aggressiveness patterns of prostate adenocarcinoma or familial history of cancers in 823 White Caucasian French men. RESULTS: Probability network according to the Markov chain algorithm separated the SNPs into two main groups: The first one was linked to the locus marked by rs6983267 and the second one was linked to the locus marked by rs1447295. When the patients were stratified according to tumor stage and prostate-specific antigen value, the association between the variant genotypes from six SNPs located in the second network and prostate cancer risk was strongest or confined to the patients from the more aggressive classes. However, the association between prostate cancer risk and the CC genotype of rs7841264, which marked the recombination hotspot at 8q24, was confined to patients with the highest Gleason score (odds ratio, 2.15; 95% confidence interval, 1.27-3.64; P=0.004). Interestingly, the G allele of rs6983267 was associated with familial prostate cancer risk. CONCLUSIONS: Our data further support that variability at 8q24 is associated with a high risk of aggressive prostate cancer at diagnosis and is linked with familial history of prostate cancer. These results corroborate that 8q24 SNPs must be evaluated in terms of prostate cancer aggressiveness markers to optimize early diagnosis procedures and management of the disease.     

Pesticide use modifies the association between genetic variants on chromosome 8q24 and prostate cancer

Genome-wide association studies have identified 8q24 region variants as risk factors for prostate cancer. In the Agricultural Health Study, a prospective study of licensed pesticide applicators, we observed increased prostate cancer risk with specific pesticide use among those with a family history of prostate cancer. Thus, we evaluated the interaction among pesticide use, 8q24 variants, and prostate cancer risk. The authors estimated odds ratios (OR) and 95% confidence intervals (95% CI) for interactions among 211 8q24 variants, 49 pesticides, and prostate cancer risk in 776 cases and 1,444 controls. The ORs for a previously identified variant, rs4242382, and prostate cancer increased significantly (P<0.05) with exposure to the organophosphate insecticide fonofos, after correction for multiple testing, with per allele ORnonexposed of 1.17 (95% CI, 0.93-1.48), per allele OR(low) of 1.30 (95% CI, 0.75-2.27), and per allele ORhigh of 4.46 (95% CI, 2.17-9.17; P-interaction=0.002, adjusted P-interaction=0.02). A similar effect modification was observed for three other organophosphate insecticides (coumaphos, terbufos, and phorate) and one pyrethroid insecticide (permethrin). Among ever users of fonofos, subjects with three or four risk alleles at rs7837328 and rs4242382 had approximately three times the risk of prostate cancer (OR, 3.14; 95% CI, 1.41-7.00) compared with subjects who had zero risk alleles and never used fonofos. We observed a significant interaction among variants on chromosome 8q24, pesticide use, and risk of prostate cancer. Insecticides, particularly organophosphates, were the strongest modifiers of risk, although the biological mechanism is unclear. This is the first report of effect modification between 8q24 and an environmental exposure on prostate cancer risk.     

Association between single nucleotide polymorphisms on chromosome 17q and the risk of prostate cancer in a Chinese population

In European populations, 7 single nucleotide polymorphisms (SNPs) on chromosome 17q, 3 SNPs on 17q12, and 4 SNPs on 17q24.3 were recently identified to be closely related to the risk of prostate cancer by a genome-wide association study. In Japanese populations, the correlation between 2 SNPs on 17q and the risk of prostate cancer and tumor aggressiveness was also confirmed by a large-scale experiment. However, whether 17q is associated with prostate cancer and its clinical manifestations in Chinese populations is still unknown. Therefore, we conducted a case-control study in a northern Chinese population and tested 2 SNPs, rs4430796 and rs1859962, on 17q in 124 prostate cancer patients and 111 controls using polymerase chain reaction-high resolution melting curve (PCR-HRM) combined with sequencing. We analyzed the association of the 2 SNPs with the risk of prostate cancer as well as patients' lifestyles, onset ages, Gleason scores, PSA levels, and pathologic stages. We found a significant difference in the G allele of SNP rs1859962 (P = 0.035, OR = 1.51, 95% CI = 1.03-2.21) but not in the rs4430796 genotype frequency or allele frequency distribution between prostate cancer patients and the controls (P > 0.05). Neither of the SNPs was significantly associated with the onset age, Gleason score, PSA level, pathologic stage, or other clinical indicators of patients with prostate cancer (P > 0.05). Our results show that polymorphism of the G allele of SNP rs1859962 is associated with the risk of prostate cancer in a Chinese population.     

Role of DNA Repair-related Gene Polymorphisms in Susceptibility to Risk of Prostate Cancer

Aim: We assessed the association between genetic variants of XPG, XPA, XPD, CSB, XPC and CCNH inthe nucleotide excision repair (NER) pathway and risk of prostate cancer. Methods: We genotyped the XPG,XPA, XPD, CSB, XPC and CCNH polymorphisms by a 384-well plate format on the MassARRAY® platform.Multivariate logistical regression analysis was used to assess the associations between the six gene polymorphismsand risk of prostate cancer. Results: Individuals carrying the XPG rs229614 TT (OR=2.01, 95%CI=1.35-3.27)genotype and T allele (OR=1.73, 95%CI=1.37-2.57) were moderately significantly associated with a higher riskof prostate cancer. Subjects with XPD rs13181 G allele had a marginally increased risk of prostate cancer, withadjusted OR(95%CI) of 1.53 (1.04-2.37). Moreover, individuals carrying with CSB rs2228526 GG genotype(OR=2.05, 95% CI=1.23-3.52) and G allele (OR=1.56, 95%CI=1.17-2.05) were associated with a higher increasedrisk of prostate cancer. The combination genotype of XPG rs2296147 T and CSB rs2228526 G allele hadaccumulative effect on the risk of this cancer, with an OR (95% CI) of 2.23(1.37-3.59). Conclusions: Our studyindicates that XPG rs2296147 and CSB rs2228526 polymorphisms are significantly associated with increasedrisk of prostate cancer, and that combination of XPG rs2296147 T allele and CSB rs2228526 G allele is stronglyassociated with an increased risk.     

CYP1B1 variants are associated with prostate cancer in non-Hispanic and Hispanic Caucasians

Cytochrome P450 1B1 (CYP1B1) is involved in the activation of many carcinogens and in the metabolism of steroid hormones. We compared allele, genotype and haplotype frequencies of six single-nucleotide polymorphisms (SNPs) within CYP1B1 among non-Hispanic Caucasians (496 cases and 498 controls) and Hispanic Caucasians (153 cases and 240 controls). In the Hispanic Caucasians, the GG genotype for rs1056836 decreased the risk for prostate cancer (PCa) when compared with the CC genotype [odds ratio (OR) = 0.31, P = 0.04, 95% confidence interval (CI) = 0.10-0.96]. Among non-Hispanic Caucasian men with more aggressive PCa, the prevalence of several SNPs (rs2567206, rs2551188, rs2617266, rs10012 and rs1056836) was significantly associated with the disease status. A common C-G-C-C-G-A haplotype for rs2567206-rs2551188-rs2617266-rs10012-rs1056836-rs1800440 showed an inverse association with PCa risk in Hispanic Caucasians (OR = 0.19, P = 0.04, 95% CI = 0.04-0.95) and with aggressive disease status (i.e. Gleason score >or=7) in non-Hispanic Caucasian cases (OR = 0.64, P = 0.008, 95% CI = 0.47-0.89). In the non-Hispanic Caucasian cases, a second major haplotype T-A-T-G-C-A was positively associated with the high-grade disease status (OR = 1.77, P = 0.002, 95% CI = 1.24-2.53). Our findings suggest that genetic polymorphisms in CYP1B1 may modify the risk for PCa and support the role of CYP1B1 as a candidate gene for PCa.     

Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis

Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all‐cause and prostate cancer‐specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high‐grade compared to low‐grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all‐cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer‐specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression.     

Association of prostate-specific antigen promoter genotype with clinical and histopathologic features of prostate cancer

The serum test for the secreted protease prostate-specific antigen (PSA) is the most widely used screening tool for prostate cancer. The PSA gene contains multiple functional and nonfunctional single nucleotide polymorphisms (SNP) in its promoter. We showed previously that the rs925013 G/A SNP, but not the rs266882 G/A SNP, was significantly associated with serum PSA in healthy men. In this study, we evaluated the association of the PSA promoter genotype with clinical data in a cohort of 1,224 men with prostate cancer. Previous work with a subset of this cohort has shown that percent high-grade (Gleason grades 4 and 5) cancer was the strongest predictor of biochemical recurrence (PSA relapse). We found a statistically significant association (P < 0.05) of the rs925013 SNP with several clinical and histomorphologic variables. The G allele was associated with higher serum PSA at diagnosis, higher percent Gleason grade 3 cancer, and lower percent high-grade and Gleason grade 4 cancer. The rs266882 SNP was modestly associated with PSA at diagnosis in a dominant model but was not associated with cancer grade. Neither SNP was associated with biochemical recurrence. The statistically significant predictors of biochemical recurrence were tumor location in the peripheral zone [odds ratio (OR), 10.71; 95% confidence interval (95% CI), 3.15-36.49], presence of any Gleason grade 4/5 cancer (OR, 4.26; 95% CI, 1.30-14.00), presence of any intraductal cancer (OR, 1.03; 95% CI, 1.00-1.04), and serum PSA at diagnosis (OR, 2.04; 95% CI, 1.50-2.77).     

Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case-control study in Chinese population

One-carbon metabolism facilitates the cross-talk between genetic and epigenetic processes, making it a good candidate for studying the risk of lung cancer. To investigate the role of common variants of one-carbon metabolizing genes on lung cancer risk, total 25 single nucleotide polymorphisms (SNPs) in 7 genes were genotyped among 500 incident lung cancer patients and 517 cancer-free controls. An increased risk was suggested for the variant allele carriers of MTHFR rs17037396 [odds ratio (OR)=1.39, 95% confidence interval (CI): 1.00-1.94] and rs3753584 (OR=1.46, 95% CI: 1.03-2.08), compared with subjects with wild homozygote, respectively, and the risk was more pronounced among older individuals (>60 years). In contrast, a decreased risk was observed for TYMS rs2853742 variant allele carriers (OR=0.44, 95% CI: 0.19-0.99) and MTHFD rs2236225 variant allele carriers (OR=0.76, 95% CI: 0.59-0.99). Haplotype analysis revealed that MTHFR "ACCACC" haplotype may contribute to the risk of lung cancer (OR=1.49, 95% CI: 1.03-2.14, local test p value 0.032). A data mining method, multifactor dimensionality reduction (MDR), predicted a four-factor interaction model (rs1801133, rs4659731, rs2273029 and rs699517) with the lowest average prediction error (45.08%, p<0.001). These findings suggest that genetic variants in one-carbon metabolizing genes might modulate the risk of lung cancer. Validation of these findings in larger studies is needed.     

Association of frequent consumption of fatty fish with prostate cancer risk is modified by COX-2 polymorphism

Dietary intake of marine fatty acids from fish may protect against prostate cancer development. We studied this association and whether it is modified by genetic variation in cyclooxygenase (COX)-2, a key enzyme in fatty acid metabolism and inflammation. We assessed dietary intake of fish among 1,499 incident prostate cancer cases and 1,130 population controls in Sweden. Five single nucleotide polymorphisms (SNPs) were identified and genotyped in available blood samples for 1,378 cases and 782 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multivariate logistic regression. Multiplicative and additive interactions between fish intake and COX-2 SNPs on prostate cancer risk were evaluated. Eating fatty fish (e.g., salmon-type fish) once or more per week, compared to never, was associated with reduced risk of prostate cancer (OR: 0.57, 95% CI: 0.43-0.76). The OR comparing the highest to the lowest quartile of marine fatty acids intake was 0.70 (95% CI: 0.51-0.97). We found a significant interaction (p < 0.001) between salmon-type fish intake and a SNP in the COX-2 gene (rs5275: +6365 T/C), but not with the 4 other SNPs examined. We found strong inverse associations with increasing intake of salmon-type fish among carriers of the variant allele (OR for once per week or more vs. never = 0.28, 95% CI: 0.18-0.45; p(trend) < 0.01), but no association among carriers of the more common allele. Frequent consumption of fatty fish and marine fatty acids appears to reduce the risk of prostate cancer, and this association is modified by genetic variation in the COX-2 gene.     

Association of HPC2/ELAC2 polymorphisms with risk of prostate cancer in a population-based study.

Genetic polymorphism in HPC2/ELAC2 was recently associated with risk of sporadic prostate cancer. To determine the contribution of two HPC2/ELAC2 missense variants (Ser217Leu and Ala541Thr) to the risk of developing prostate cancer, we conducted a population-based case-control study of middle-aged men (40-64 years). Cases (n=591) were ascertained from the Seattle-Puget Sound Surveillance, Epidemiology, and End Results Cancer Registry and Controls (n=538) from the same general population were identified through random-digit dialing. Subjects were residents of King County, Washington, and were frequency matched on age. Cases (32%) had a slightly higher frequency of the Leu217 variant compared with controls (29%), but there were no differences in the frequency of the Thr541 allele (4%). When considering joint genotypes, white men homozygous for the Leu217 variant on an Ala541/Ala541 background had an increased risk of prostate cancer [odds ratio (OR)=1.84; 95% confidence interval (CI), 1.11-3.06]. Different risk profiles were also observed when cases were stratified by disease aggressiveness. Men with at least one Leu217 allele had an elevated risk (OR=1.34; 95% CI, 1.02-1.76) of less aggressive prostate cancer (localized stage and Gleason score < or = 7), with a stronger association among men with two Leu217 alleles (OR=1.73; 95% CI, 1.08-2.77). The Ala541Thr polymorphism was not associated with risk, and neither variant was associated with more aggressive prostate cancer phenotypes. We estimate that the Ser217Leu genotype may account for approximately 14% of less aggressive prostate cancer cases and 9% of all sporadic cases in the general United States population of white men 相似文献