Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate-specific antigen (PSA) level: a meta-analysis.

OBJECTIVE: To review and quantify the association between endogenous and exogenous testosterone and prostate-specific antigen (PSA) and prostate cancer. METHODS: Literature searches were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Prospective cohort studies that reported data on the associations between endogenous testosterone and prostate cancer, and placebo-controlled randomized trials of testosterone replacement therapy (TRT) that reported data on PSA and/or prostate cancer cases were retained. Meta-analyses were performed using random-effects models, with tests for publication bias and heterogeneity. RESULTS: Twenty estimates were included in a meta-analysis, which produced a summary relative risk (SRR) of prostate cancer for an increase of 5 nmol/L of testosterone of 0.99 (95% confidence interval [CI] 0.96, 1.02) without heterogeneity (I² = 0%). Based on 26 trials, the overall difference in PSA levels after onset of use of TRT was 0.10 ng/mL (-0.28, 0.48). Results were similar when conducting heterogeneity analyses by mode of administration, region, age at baseline, baseline testosterone, trial duration, type of patients and type of TRT. The SRR of prostate cancer as an adverse effect from 11 TRT trials was 0.87 (95% CI 0.30; 2.50). Results were consistent across studies. CONCLUSIONS: Prostate cancer appears to be unrelated to endogenous testosterone levels. TRT for symptomatic hypogonadism does not appear to increase PSA levels nor the risk of prostate cancer development. The current data are reassuring, although some caution is essential until multiple studies with longer follow-up are available.

Human blood plasma proteome mapping for search of potential markers of the lung squamous cell carcinoma.

Blood plasma proteomes obtained from 77 lung squamous cell carcinoma (LSCC) patients (Stages I-III) and 67 healthy controls (all males) were analyzed by using the label-free liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the search of potential cancer biomarkers. All plasma samples were depleted of 14 highly-abundant plasma proteins by immune-affinity column chromatography before LC-MS/MS. We identified and quantified 809 differential proteins with molecular weights from 6.4 kDa to 3900 kDa using a label-free method. Three hundred and sixty four proteins were identified in all three groups. Changes in levels of an expression of blood plasma proteins associated with LSCC were discovered. Among them, 43 proteins were overexpressed and 39 proteins were down-regulated by more than two-fold between the plasmas of lung cancer patients and healthy men. We focused our attention on proteins whose expression levels increased from control to early stage and then to advanced stage tumor. Each of the 43 unique overexpressed proteins was classified according to its cellular localization, biological processes, molecular function and classes. Many of these proteins are involved in biological pathways pertinent to tumor progression and metastasis and some of these deregulated proteins may be useful clinical markers.

Cancer mortality among female and male workers occupationally exposed to inorganic lead in the printing industry.

OBJECTIVE: Evaluation of the carcinogenicity of lead for humans has been based primarily on the results of studies on occupationally exposed men, although gender differences in lead metabolism have been reported. In addition, most of the previous studies have been limited by a failure to identify and control for co-exposures to other known occupational carcinogens. The present study follows an industrial cohort of workers, mostly women, with moderate lead exposure and no confounding by other occupational exposures. METHODS: Workers, employed at least 2 years between 1950 and 1978 in manual and mechanical (linotype) typesetting and type foundries in 27 printing plants in Moscow, were included in the cohort, which comprised 1423 men and 3102 women. The cohort was followed up during 1979-2003 and contributed 93,682 person-years of observation. Follow-up was 97.7% complete. Standardised mortality ratios (SMRs) and 95% CIs, based on mortality rates of the Moscow general population and adjusted for gender, age and calendar time, were calculated for the total cohort as well as subcohorts stratified by various exposure parameters. RESULTS: Among women, mortality from all causes, circulatory diseases and all cancers combined was lower than that in the Moscow general population and was similar across work groups. Among men, there was excess overall mortality, mainly due to increased mortality from ischaemic heart disease. For both sexes, no significant excess risk for any cancer site was observed, although some dose-response patterns were found. In the overall cohort, mortality from cancers of the kidney and pancreas increased up to twofold in the highest tertile of cumulative lead exposure based on duration and a relative ranking of the three subcohorts (9 deaths; SMR=2.12, 95% CI 1.10 to 4.07) and (18 deaths; SMR=2.32, 95% CI 1.46 to 3.68), respectively. Similar mortality trends for these two cancers were found in analyses by gender. CONCLUSIONS: Consistencies by sex and exposure level make a strong case for a link between exposure to inorganic lead and cancers of the kidney and pancreas.

Detection of lung cancer using plasma protein profiling by matrix-assisted laser desorption/ionization mass spectrometry.

There are no satisfactory plasma biomarkers which are available for the early detection and monitoring of lung cancer, one of the most frequent cancers worldwide. The aim of this study is to explore the application of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF MS) to plasma proteomic patterns to distinguish lung cancer patients from healthy individuals. The EDTA plasma samples have been pre-fractionated using magnetic bead kits functionalized with weak cation exchange coatings. We compiled MS protein profiles for 90 patients with squamous cell carcinomas (SCC) and compared them with profiles from 187 healthy controls. The MALDI-ToF spectra were analyzed statistically using ClinProTools bioinformatics software. Depending on the sample used, up to 441 peaks/spectrum could be detected in a mass range of 1000-20,000 Da; 33 of these proteins had statistically differential expression levels between SCC and control plasma (P < 0.001). The series of the peaks were automatically chosen as potential biomarker patterns in the training set. They allowed the discrimination of plasma samples from healthy control and samples from SCC patients (sensitivity and specificity >90%) in external validation test. These results suggest that plasma MALDI-ToF MS protein profiling can distinguish patients with SCC and also from healthy individuals with relatively high sensitivity and specificity and that MALDI- ToF MS is a potential tool for the screening of lung cancer.

TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers.

TP53 mutations are common in lung cancers of smokers, with high prevalence of G:C-to-T:A transversions generally interpreted as mutagen fingerprints of tobacco smoke. In this study, TP53 (exons 5-9) and KRAS (codon 12) were analyzed in primary lung tumors of never (n = 40), former (n = 27), and current smokers (n = 64; mainly heavy smokers). Expression of p53, cyclooxygenase-2 (Cox-2), and nitrotyrosine (N-Tyr), a marker of protein damage by nitric oxide, were analyzed by immunohistochemistry. TP53 mutations were detected in 47.5% never, 55.6% former, and 77.4% current smokers. The relative risk for mutation increased with tobacco consumption (P(linear trend) < 0.0001). G:C-to-T:A transversions (P = 0.06, current versus never smokers) and A:T-to-G:C transitions (P = 0.03, former versus never smokers) were consistently associated with smoking. In contrast, G:C-to-A:T transitions were associated with never smoking (P = 0.02). About half of mutations in current smokers fell within a particular domain of p53 protein, suggesting a common structural effect. KRAS mutations, detected in 20 of 131 (15.3%) cases, were rare in squamous cell carcinoma compared with adenocarcinoma [relative risk (RR), 0.2; 95% confidence interval (95% CI), 0.07-1] and were more frequent in former smokers than in other categories. No significant differences in Cox-2 expression were found between ever and never smokers. However, high levels of N-Tyr were more common in never than ever smokers (RR, 10; 95% CI, 1.6-50). These results support the notion that lung tumorigenesis proceeds through different molecular mechanisms according to smoking status. In never smokers, accumulation of N-Tyr suggests an etiology involving severe inflammation.

Xenobiotic metabolizing gene variants and renal cell cancer: a multicenter study.

BACKGROUND: The countries of Central and Eastern Europe have among the highest worldwide rates of renal cell cancer (RCC). Few studies have examined whether genetic variation in xenobiotic metabolic pathway genes may modify risk for this cancer. METHODS: The Central and Eastern Europe Renal Cell Cancer study was a hospital-based case-control study conducted between 1998 and 2003 across seven centers in Central and Eastern Europe. Detailed data were collected from 874 cases and 2053 controls on demographics, work history, and occupational exposure to chemical agents. Genes [cytochrome P-450 family, N-acetyltransferases, NAD(P)H: quinone oxidoreductase I (NQO1), microsomal epoxide hydrolase (mEH), catechol-O-methyltransferase (COMT), uridine diphosphate-glucuronosyltransferase (UGT)] were selected for the present analysis based on their putative role in xenobiotic metabolism. Haplotypes were calculated using fastPhase. Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression adjusted for country of residence, age, sex, smoking, alcohol intake, obesity, and hypertension. RESULTS: We observed an increased risk of RCC with one SNP. After adjustment for multiple comparisons it did not remain significant. Neither NAT1 nor NAT2 slow acetylation was associated with disease. CONCLUSION: We observed no association between this pathway and renal cell cancer.