Variant NKX3.1 and Serum IGF-1: Investigation of Interaction in Prostate Cancer.

NKX3.1 is a tumor suppressor down-regulated in early prostate cancers. A SNP (rs2228013), which represents a polymorphic NKX3.1(C154T) coding for a variant protein NKX3.1(R52C), is present in 10% of the population and is related to prostatic enlargement and prostate cancer. We investigated rs2228013 in prostate cancer risk for 937 prostate cancer cases and 1,086 age-matched controls from a nested case-control study within the prospective Physicians' Health Study (PHS) and among 798 cases and 527 controls retrospectively collected in the Risk Factors for Prostate Cancer Study of the Victoria Cancer Council (RFPCS). We also investigated the interaction between serum IGF-I levels and NKX3.1 genotype in the populations from PHS and RFPCS. In the PHS, we found no overall association between the variant T allele in rs2228013 in NKX3.1 and prostate cancer risk (odd ratio = 1.25; 95% confidence interval = 0.92-1.71). A subgroup analysis for cases diagnosed before age 70 showed an increased risk (relative risk = 1.55; 95% confidence interval = 1.04-2.31) of overall prostate cancer. In this age-group, the risk of metastatic cancer at diagnosis or of fatal cancer was even higher in carriers of the T allele (relative risk = 2.15; 95% confidence interval = 1.00-4.63). These associations were not replicated in the RFPCS. Serum IGF-I levels were found to be a risk factor for prostate cancer in both study populations. The wild type NKX3.1 protein can induce IGFBP-3 expression in vitro. We report that variant NKX3.1 cannot induce IGFBP-3 expression, but the NKX3.1 genotype does not modify the association between serum IGF-I levels and prostate cancer risk.

Interleukin-6 promoter variants, prostate cancer risk, and survival.

BACKGROUND: Inflammation has been implicated in prostate cancer (PCa) pathogenesis. Promoter DNA variants responsible for differential expression of key cytokines may therefore influence susceptibility to PCa. METHODS: Two interleukin-6 (IL-6) promoter variants, -174G>C and -6331T>C, were genotyped for association with PCa risk and survival using the Risk Factors for Prostate Cancer Study (RFPCS, 825 cases and 732 controls) and the Melbourne Collaborative Cohort Study (MCCS, 818 cases and 1,745 controls). Impact of genotypes on IL-6 transcriptional activity was measured using Low Density Arrays. RESULTS: A significant increase in IL-6 transcriptional activity in malignant compared to benign prostate tissue supports a role for IL-6 in PCa. The -174G>C variant showed no association with PCa risk, overall survival, or IL-6 transcriptional activity. The -6331 C-allele was significantly associated with an increased risk in the RFPCS (OR = 1.29, 95% CI = 1.08-1.54), but not in the MCCS. In the MCCS however, cases presenting with a CC genotype conferred a higher risk of mortality (HR = 2.27, 95% CI = 1.34-3.85), which was maintained although reduced overall in the pooled analysis with RFPCS (HR = 1.68, 95% CI = 1.10-2.54). Furthermore, we associate the minor C-allele with a significant decrease in IL-6 transcriptional activity. CONCLUSIONS: While our study refutes a role for IL-6 -174G>C, it is the first to implicate -6331T>C with PCa risk and poor survival. Our observation that -6331T>C has a significant impact on IL-6 transcriptional activity, calls for further investigations into the role of this variant as a novel PCa biomarker.

Weight change and prostate cancer incidence and mortality.

The relationship between obesity and prostate cancer risk has been studied extensively but with inconsistent findings, particularly for tumor aggressiveness. Few studies have investigated weight change and prostate cancer incidence or mortality. Using the Melbourne Collaborative Cohort Study, which recruited 17,045 men aged between 40 and 69 years at study entry, we investigated associations between reported weight and body mass index (BMI) at age 18 and measured at study entry, height, weight change between age 18 and study entry and prostate cancer incidence and mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression. During follow-up (mean = 15 years) of 16,514 men, we ascertained 1,374 incident prostate cancers of which 410 were classified as aggressive, and 139 deaths from prostate cancer. The incidence of all prostate cancer was not associated with body size or weight change. Weight and BMI at study entry were positively associated with aggressive prostate cancer risk (HR = 1.06, 95% CI: 1.00-1.13 per 5 kg; HR = 1.27, 95% CI: 1.08-1.49 per 5 kg/m(2)) and prostate cancer mortality (HR = 1.12, 95% CI: 1.01-1.23 per 5 kg; HR = 1.49, 95% CI: 1.11-2.00 per 5 kg/m(2)). Weight gain was positively associated with prostate cancer mortality (HR = 1.13, 95% CI: 1.02-1.26 per 5 kg increment); the HR for ≥ kg weight gain between age 18 and study entry compared to <5 kg gain over this period was 1.84, 95% CI: 1.09-3.09. Higher adult weight and BMI increases the risk of aggressive prostate cancer and mortality from prostate cancer. Weight gain during adult life is associated with increased prostate cancer mortality.

The 4q27 locus and prostate cancer risk.

BACKGROUND: Chronic inflammation is considered to be implicated in the development of prostate cancer. In this study we are the first to investigate a potential association between variants in an autoimmune related region on chromosome 4q27 and prostate cancer risk. This region harbors two cytokine genes IL-2 and the recently described IL-21. METHODS: We genotyped six variants previously associated with autoimmune disease (namely rs13151961, rs13119723, rs17388568, rs3136534, rs6822844 and rs6840978) and one functional IL-2 promoter variant (rs2069762) for possible association with prostate cancer risk using the Australian Risk Factors for Prostate Cancer case-control Study. RESULTS: Overall, our results do not support an association between the seven variants at position 4q27 and prostate cancer risk. Per allele odds ratios (ORs) were not significantly different from 1 (all P-values = 0.06). However, we found suggestive evidence for a significant association between the presence of the rs13119723 variant (located in a protein of unknown function) and men with a family history of prostate cancer in first-degree relatives (P-value for interaction 0.02). The per allele OR associated with this variant was significantly higher than 1 (2.37; 95% C.I. = 1.01-5.57). CONCLUSIONS: We suggest that genetic variation within the chromosome 4q27 locus might be associated with prostate cancer susceptibility in men with a family history of the disease. Furthermore, our study alludes to a potential role of unknown protein KIAA1109 in conferring this risk.

Cyclin D1 splice variants: polymorphism, risk, and isoform-specific regulation in prostate cancer.

PURPOSE: Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged. EXPERIMENTAL DESIGN: First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies. RESULTS: Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed noncorrelated expression patterns, and hormone status did not alter splicing. Whereas G/A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism. CONCLUSIONS: These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict cancer risk, tumor cells can bypass the influence of the polymorphism. These findings have major implications for the analyses of D-cyclin function in the prostate and provide the foundation for future studies directed at identifying potential modifiers of the G/A870 polymorphism.

No association between common chemokine and chemokine receptor gene variants and prostate cancer risk.

There is growing evidence that inflammation and infection play important roles in the etiology of prostate cancer. As the chemokine network is directly involved in inflammation and infectious diseases, we tested for an association between six common putative functional variants and prostate cancer risk using an Australian case-control study. We measured CCL5 -403G>A, CXCL12 +801G>A, CCR2V64I (G>A), CCR5Delta32, CX3CR1V249I (G>A), and CX3CR1T280M (C>T) for 815 cases and 738 controls. Of these, only CXCL12 +801G>A has previously been tested and found to be associated with prostate cancer risk. We found no significant associations with prostate cancer risk (all P > 0.4). All per allele odds ratios ranged from 0.96 (95% confidence intervals, 0.80-1.16) to 1.06 (95% confidence intervals, 0.90-1.23). This suggests that these common chemokine and chemokine receptor variants do not play a major, if any, role in susceptibility to prostate cancer.

The rs743572 common variant in the promoter of CYP17A1 is not associated with prostate cancer risk or circulating hormonal levels.

OBJECTIVE: To use a large population-based case-control study to test the association between the common genetic variant rs743572 (-34 T to C), prostate cancer risk and circulating levels of several hormones. SUBJECTS AND METHODS: A previous meta-analysis concluded that reported associations between rs743572 in the promoter of CYP17A1 and prostate cancer risk might reflect publication bias, but a few recent studies reported associations with prostate cancer risk and data suggesting that rs743572 is functional. We genotyped 824 prostate cancer cases and 737 population-based controls, and applied unconditional logistic regression to estimate the association between rs743572 and prostate cancer risk. We also used linear regression of transformed testosterone, androstanediol glucuronide, dehydroepiandrosterone sulphate, androstenedione, sex hormone-binding globulin and oestradiol (circulating levels) measured for controls, to estimate the association between these levels and rs743572. The linear models were adjusted for age and laboratory batch. RESULTS: Men with different genotypes had similar circulating levels of all the hormones measured (all P < 0.05). In the case-control comparison using unconditional unadjusted logistic regression, the odds ratios (95% confidence interval) for prostate cancer were 1.07 (0.87-1.32) and 0.94 (0.71-1.25) for the dominant and recessive models, respectively, and for the co-dominant model, 1.10 (0.88-1.36) and 0.99 (0.73-1.35) for carriers of one or two copies of the C allele, respectively. There was no evidence of heterogeneity in the odds ratios by tumour stage (all P > 0.3) and grade (all P > 0.3). CONCLUSION: The results of the present study are consistent with the conclusions of the previous meta-analysis, and suggest that rs743572 has no role in the risk of prostate cancer for men of Caucasian origin.