Single-nucleotide polymorphisms within the antioxidant defence system and associations with aggressive prostate cancer.

OBJECTIVE: To study the effects of oxidative stress on prostate cancer development as the exact biological mechanisms behind the relationship remain uncertain. We previously reported a statistically significant interaction between circulating selenium levels, variants in the superoxide dismutase 2 gene (SOD2; rs4880), and risk of developing prostate cancer and presenting with aggressive prostate cancer. PATIENTS AND METHODS: We genotyped men with localized/regional prostate cancer for 26 loci across eight genes that are central to cellular antioxidant defence: glutathione peroxidase (GPX1, GPX4), peroxisome proliferator-activated receptor γ coactivator (PPARGC1A, PPARGC1B), SOD1, SOD2, and SOD3, and 'X-ray repair complementing defective repair in Chinese hamster cell 1' (XRCC1). Among 489 men, we examined the relationships between genotypes, circulating selenium levels, and risk of presenting with aggressive prostate cancer at diagnosis, as defined by stage, grade and prostate-specific antigen (PSA) level (213 aggressive cases). RESULTS: Two variants in SOD2 were significantly associated with the risk of aggressive prostate cancer (rs17884057, odds ratio 0.83, 95% confidence interval 0.70-0.99; and rs4816407, 1.27, 1.02-1.57); men with A alleles at rs2842958 in SOD2 had lower plasma selenium levels (median 116 vs 121.8 µg/L, P= 0.03); and the association between plasma selenium levels and risk of aggressive prostate cancer was modified by SOD1 (rs10432782) and SOD2 (rs2758330). CONCLUSION: While this study was cross-sectional and these associations might be due to chance, further research is warranted on the potential important role of antioxidant defence in prostate cancer.

Polymorphism in endostatin, an angiogenesis inhibitor, and prostate cancer risk and survival: A prospective study.

Endostatin inhibits endothelial cell proliferation and migration, prerequisites of angiogenesis. A functional missense mutation (D104N) in endostatin was associated with an increased prostate cancer risk in a small study. We undertook a larger, prospective study within the Physicians' Health Study to examine D104N and prostate cancer risk and progression among 544 incident prostate cancer cases (1982-1995) and 678 matched controls. The association between endostatin genotype and cancer risk was estimated using logistic regression models. Among cases, Cox models were used to assess D104N and lethal prostate cancer. Given the role of endostatin in neovascularization of adipose tissue, we cross classified individuals on D104N genotype and body mass index (BMI). The genotype frequency was 1.3% homozygous (NN), 14.5% heterozygous (DN) and 84.2% wildtype homozygous (DD). There was no overall association between carriage of the N allele and prostate cancer risk (RR = 1.2, 95% CI: 0.9-1.6) or cancer-specific mortality (HR = 1.2, 0.7-1.8). Cases with the polymorphic allele were less likely to be overweight (BMI 25 kg/m(2) or greater, 26%) compared to men wildtype homozygous (48%), p < 0.0001. Being overweight was associated with a 60% greater prostate cancer risk among those who were wildtype homozygous. In contrast, being overweight was associated with a 50% lower risk of cancer among those with the N allele. We did not confirm an earlier observation between the D104N polymorphism and prostate cancer. However, our data indicate that prostate cancer cases who carry the variant N allele are more likely to be overweight, and may be more susceptible to the angiogenic influences of obesity in prostate cancer pathogenesis.

Prostate cancer risk and ESR1 TA, ESR2 CA repeat polymorphisms.

BACKGROUND: Experimental evidence has suggested that estrogen receptor alpha (coded by the gene ESR1) might increase prostate cancer risk, whereas estrogen receptor beta (coded by the gene ESR2) might reduce prostate cancer risk. METHODS: We investigated the relationship with prostate cancer risk of both a TA repeat polymorphism in the ESR1 5' region, ESR1 (TA)(n), and with a CA repeat polymorphism in intron 5 of ESR2, ESR2 (CA)(n), in a case-control study (545 cases and 674 controls) nested in the Physicians' Health Study. RESULTS: Prostate cancer risk was highest for carriers of ESR1 (TA)(24) and ESR1 (TA)(25). Replacing one modal ESR1 (TA)(14) allele with one ESR1 (TA)(24) allele yielded an odds ratio of 1.42 (95% confidence interval, 1.00-2.00; P=0.05). Replacing one ESR1 (TA)(14) allele with one ESR1 (TA)(25) allele yielded an odds ratio of 2.10 (95% confidence interval, 1.15-3.84; P=0.02). ESR2 (CA)(n) showed no effects on prostate cancer risk. CONCLUSIONS: The ESR1 (TA)(n) polymorphism might play a role in prostate cancer risk.

Mutations in ribonuclease L gene do not occur at a greater frequency in patients with familial prostate cancer compared with patients with sporadic prostate cancer.

Several genetic loci are suspected to be involved in hereditary prostate cancer, including the hereditary prostate cancer 1 (HPC1) locus at chromosome 1q24-25. The ribonuclease L (RNase L) gene has been reported as the putative hereditary prostate cancer gene located at HPC1. If this is the case, mutations of RNase L should be found at a greater frequency in familial cancers than in sporadic prostate cancers. Examination of familial and sporadic cases of prostate cancer by polymerase chain reaction and DNA sequencing resulted in a mutational frequency rate that was not statistically different between the 2 forms of the disease. These results suggest that the mutations examined within this study are rare and may contribute to very few familial prostate cancers.

Plasma levels of heat shock protein 70 in patients with prostate cancer: a potential biomarker for prostate cancer.

Heat shock protein 70 (Hsp70) is a stress-inducible protein that is also known for its inhibitory effects on apoptosis. Increased Hsp70 expression is reported in a variety of tumor tissues. Heat shock protein 70 is detectable in plasma and could potentially be used as a biomarker for diagnosis or disease stratification. The relationship between plasma levels of Hsp70 and prostate cancer status has not been well studied. Our study was designed to test this relationship. One hundred twenty-five patients with localized/untreated or hormone-refractory prostate cancer were identified. Forty-five healthy male blood donors between 50 and 73 years of age served as controls. EDTA plasma was subjected to quantitative sandwich immunoassays for both Hsp70 and prostate-specific antigen (PSA). Wilcoxon rank-sum tests were used to examine differences by category. Maximally selected c2 statistics were used to identify cutoff points to best distinguish between categories. Plasma Hsp70 levels in the patients with localized untreated disease (n = 68; median, 0.8 ng/mL; interquartile range, 0.5-2.0) were significantly higher than those in the control group (n = 45; median, 0.5 ng/mL; interquartile range, 0.3-0.8; P = 0.0037). Although the primary cutoff point (1.15 ng/mL) significantly distinguished the localized untreated patients from the control group, plasma Hsp70 levels did not prove more effective than PSA as a predictor for diagnosis or stratification of patients with prostate cancer in the context of group comparisons. Nonetheless, several patients in the localized untreated group showed higher plasma levels of Hsp70 than the primary cutoff point even though their PSA levels were within normal range (< 4 ng/mL). Heat shock protein 70 is a marker of prostate cancer, although its clinical utility is uncertain. It is possible that when used in conjunction with PSA it might prove useful in identifying patients with early-stage prostate cancer who might otherwise be missed by PSA screening alone.

Plasma selenium, manganese superoxide dismutase, and intermediate- or high-risk prostate cancer.

PURPOSE: In vitro, in vivo, and epidemiologic studies support a role for selenium in reducing the risk of prostate cancer. Our group previously demonstrated a strong interaction between plasma selenium and the manganese superoxide dismutase (SOD2) gene and incident prostate cancer risk. We now hypothesized that SOD2 modifies the association between selenium level and risk of aggressive prostate cancer at diagnosis. PATIENTS AND METHODS: We assessed SOD2 variants and plasma selenium in 489 patients with localized/locally advanced prostate cancer from an ongoing retrospective cohort. Cross-sectional associations with aggressive prostate cancer (ie, stage T2b-3, prostate-specific antigen > 10 ng/mL, or biopsy Gleason score > or = 7) were evaluated using the chi(2) test, Cochran-Armitage test for trend, and estimations of relative risk (RR) and 95% CIs. RESULTS: SOD2 genotype alone was not associated with disease aggressiveness, whereas higher versus lower selenium levels were associated with a slightly increased likelihood of presenting with aggressive disease (RR = 1.35; 95% CI, 0.99 to 1.84). There was evidence of an interaction between SOD2 and selenium levels such that among men with the AA genotype, higher selenium levels were associated with a reduced risk of presenting with aggressive disease (RR = 0.60; 95% CI, 0.32 to 1.12), whereas among men with a V allele, higher selenium levels were associated with an increased risk of aggressive disease (for VV or VA men, RR = 1.82; 95% CI, 1.27 to 2.61; P for interaction = .007). CONCLUSION: These data suggest that the relationship between circulating selenium levels at diagnosis and prognostic risk of prostate cancer is modified by SOD2 genotype and indicate caution against broad use of selenium supplementation for men with prostate cancer.

Effects of menstrual cycle and physical training on heat loss responses during dynamic exercise at moderate intensity in a temperate environment.

We evaluated the effects of the menstrual cycle and physical training on heat loss (sweating and cutaneous vasodilation) responses during moderate exercise in a temperate environment. Ten untrained (group U) and seven endurance-trained (group T) women (maximal O2 uptake of 36.7+/-1.1 vs. 49.4+/-1.7 ml.kg-1.min-1, respectively; P<0.05) performed a cycling exercise at 50% maximal O2 uptake for 30 min during both the midfollicular and midluteal menstrual phase in a temperate environment (ambient temperature of 25 degrees C, relative humidity of 45%). In group U, plasma levels of estrone, estradiol, and progesterone at rest and esophageal temperature (Tes) during exercise were significantly higher during the midluteal than during the midfollicular phase (P<0.05). Sweating rate and cutaneous blood flow (measured via laser-Doppler flowmetry) on the chest, back, forearm, and thigh were lower during the midluteal than during the midfollicular phase during exercise. Tes threshold for heat loss responses was significantly higher and sensitivity of the heat loss responses was significantly lower in the midluteal than in the midfollicular phase, regardless of body site. These effects of the menstrual cycle in group U were not observed in group T. The sweating rate and cutaneous blood flow were significantly higher in group T than in group U, regardless of menstrual phase or body site. Tes threshold for heat loss responses was significantly lower and sensitivity of heat loss responses was significantly greater in group T than in group U in the midluteal phase; however, sensitivity of the sweating response was significantly greater in the midfollicular phase. These results suggest that heat loss responses in group U were inhibited in the midluteal phase compared with in the midfollicular phase. Menstrual cycle had no remarkable effects in group T. Physical training improved heat loss responses, which was more marked in the midluteal than in the midfollicular phase.