Exposure to environmental pollutants and genetic variants related to oxidative stress and xenobiotic metabolism-Association with prostate cancer.

This study assessed whether genetic variants coding for certain enzymes involved in xenobiotic detoxification, antioxidant defences and DNA repair, along with exposure to environmental chemicals, were associated with an increased prostate cancer (PCa) risk. The study population consisted of 300 men (150 PCa cases and 150 controls) which underwent prostate biopsy as their serum prostate specific antigen (PSA) levels were greater than 4 ng/ml. Genetic variants in GSTM1, GSTP1, SOD2, CAT, GPX1, XRCC1 were determined and data for chemical exposures was obtained through a structured questionnaire and by biomonitoring in a subsample of cases and controls. High serum PSA levels were associated with a greater risk of PCa, while physical exercise appears to exert a protective effect against its development. In addition, elevated urinary levels of certain organic pollutants, such as benzo(a)pyrene (BaP), bisphenol A (BPA), and ethyl-paraben (EPB), were associated with an increased risk of PCa.

Explainable artificial intelligence to predict and identify prostate cancer tissue by gene expression.

BACKGROUND AND OBJECTIVE: Prostate cancer is one of the most prevalent forms of cancer in men worldwide. Traditional screening strategies such as serum PSA levels, which are not necessarily cancer-specific, or digital rectal exams, which are often inconclusive, are still the screening methods used for the disease. Some studies have focused on identifying biomarkers of the disease but none have been reported for diagnosis in routine clinical practice and few studies have provided tools to assist the pathologist in the decision-making process when analyzing prostate tissue. Therefore, a classifier is proposed to predict the occurrence of PCa that provides physicians with accurate predictions and understandable explanations. METHODS: A selection of 47 genes was made based on differential expression between PCa and normal tissue, GO gene ontology as well as the literature to be used as input predictors for different machine learning methods based on eXplainable Artificial Intelligence. These methods were trained using different class-balancing strategies to build accurate classifiers using gene expression data from 550 samples from 'The Cancer Genome Atlas'. Our model was validated in four external cohorts with different ancestries, totaling 463 samples. In addition, a set of SHapley Additive exPlanations was provided to help clinicians understand the underlying reasons for each decision. RESULTS: An in-depth analysis showed that the Random Forest algorithm combined with majority class downsampling was the best performing approach with robust statistical significance. Our method achieved an average sensitivity and specificity of 0.90 and 0.8 with an AUC of 0.84 across all databases. The relevance of DLX1, MYL9 and FGFR genes for PCa screening was demonstrated in addition to the important role of novel genes such as CAV2 and MYLK. CONCLUSIONS: This model has shown good performance in 4 independent external cohorts of different ancestries and the explanations provided are consistent with each other and with the literature, opening a horizon for its application in clinical practice. In the near future, these genes, in combination with our model, could be applied to liquid biopsy to improve PCa screening.

Genetic variants of antioxidant and xenobiotic metabolizing enzymes and their association with prostate cancer: A meta-analysis and functional in silico analysis.

The development and progression of prostate cancer (PCa) depends on complex interactions between genetic, environmental and dietary factors that modulate the carcinogenesis process. Interactions between chemical exposures and genetic polymorphisms in genes encoding xenobiotic metabolizing enzymes (XME), antioxidant enzymes and DNA repair enzymes have been reported as the main drivers of cancer. Thus, a better understanding of the causal risk factors for PCa will provide avenues to identify men at increased risk and will contribute to develop effective detection and prevention methods. We performed a meta-analysis on 17,518 cases and 42,507 controls obtained from 42 studies to determine whether seven SNPs and one CNV pertaining to oxidative stress, xenobiotic detoxification and DNA repair enzymes are associated with the risk of PCa (GPX1 (rs1050450), XRCC1 (rs25487), PON1 (rs662), SOD2 (rs4880), CAT (rs1001179), GSTP1 (rs1695) and CNV GSTM1). A significant increased risk of PCa was found for SOD2 (rs4880) ORGG+GA vs. AA 1.08; 95%CI 1.01-1.15, CAT (rs1001179) ORTT vs. TC+CC 1.39; 95%CI 1.17-1.66, PON1 (rs662) ORCT vs. CC+TT 1.17; 95%CI 1.01-1.35, GSTP1 (rs1695) ORGG vs. GA+AA 1.20; 95%CI 1.05-1.38 and GSTM1 (dual null vs. functional genotype) ORN vs. NN1+NN2 1.34; 95%CI 1.10-1.64. The meta-analysis showed that the CNV GSTM1, and the SNPs GSTP1 (rs1695) and CAT (rs1001179) are strongly associated with a greater risk of PCa and, to a lesser extent, the genetic variants SOD2 (rs4880) and PON1 (rs662). Although several antioxidant enzymes and XME play an important role in the PCa development, other risk factors such as chemical exposures should also be considered to gain insight on PCa risk. The functional in silico analysis showed that the genetic variants studied had no clinical implication regarding malignancy, except for GPX1 (rs1050450) SNP.

The Influence of Exercise, Lifestyle Behavior Components, and Physical Fitness on Maternal Weight Gain, Postpartum Weight Retention, and Excessive Gestational Weight Gain.

This study examines (a) the influence of exercise, lifestyle behavior components (sedentary time, physical activity, and sleep and dietary patterns), and physical fitness on maternal weight gain, postpartum weight retention, and excessive gestational weight gain and (b) whether exercise protects against the adverse effects of impaired metabolism and nonoptimal body composition related to excessive gestational weight gain. Subjects were assigned to either a supervised concurrent (aerobic + resistance) exercise program followed 3 days/week (n = 47) or a control group (n = 54). Sedentary time, physical activity, sleep and dietary patterns (assessed by accelerometry and questionnaires), muscle strength (handgrip test), and cardiorespiratory fitness (Bruce test) were determined at gestational Weeks 16 and 33 (early-middle and late pregnancy, respectively), and at 6 weeks postpartum. Weight gain and weight retention were calculated using recorded weights at prepregnancy, early-middle, and late pregnancy, and at 6 weeks postpartum. Birth complications, maternal postpartum body composition, cardiometabolic, and inflammatory markers in maternal and umbilical cord arterial and venous blood, and in colostrum, and mature milk were also recorded. The exercise intervention reduced late weight gain (B = -2.7, SE = 0.83, p = .003) and weight retention (B = -2.85, SE = 1.3, p = .03), independent of any lifestyle behavior component or physical fitness, but did not prevent excessive weight gain. Increasing cardiorespiratory fitness, muscle strength, and sleep duration were associated with a smaller mean weight gain and lower excessive weight gain values (p < .05). Among the participants who experienced excessive weight gain, those who were exercisers had a lower body mass index and systemic tumor necrosis factor-alpha concentration, lower umbilical cord venous tumor necrosis factor-alpha and arterial interferon gamma levels, higher cord arterial interleukin-10 levels, and improved placental function compared with controls (p < .05). In summary, exercise may help optimize gestational weight gain and weight retention, and may attenuate the impaired phenotype related to excessive weight gain. Increasing cardiorespiratory fitness, muscle strength, and sleep duration might help to prevent excessive weight gain during pregnancy.

Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis.

In this study, we have evaluated whether 57 genome-wide association studies (GWAS)-identified common variants for type 2 diabetes (T2D) influence the risk of developing prostate cancer (PCa) in a population of 304 Caucasian PCa patients and 686 controls. The association of selected single nucleotide polymorphisms (SNPs) with the risk of PCa was validated through meta-analysis of our data with those from the UKBiobank and FinnGen cohorts, but also previously published genetic studies. We also evaluated whether T2D SNPs associated with PCa risk could influence host immune responses by analysing their correlation with absolute numbers of 91 blood-derived cell populations and circulating levels of 103 immunological proteins and 7 steroid hormones. We also investigated the correlation of the most interesting SNPs with cytokine levels after in vitro stimulation of whole blood, peripheral mononuclear cells (PBMCs), and monocyte-derived macrophages with LPS, PHA, Pam3Cys, and Staphylococcus Aureus. The meta-analysis of our data with those from six large cohorts confirmed that each copy of the FTOrs9939609A, HNF1Brs7501939T, HNF1Brs757210T, HNF1Brs4430796G, and JAZF1rs10486567A alleles significantly decreased risk of developing PCa (p = 3.70 × 10-5, p = 9.39 × 10-54, p = 5.04 × 10-54, p = 1.19 × 10-71, and p = 1.66 × 10-18, respectively). Although it was not statistically significant after correction for multiple testing, we also found that the NOTCH2rs10923931T and RBMS1rs7593730 SNPs associated with the risk of developing PCa (p = 8.49 × 10-4 and 0.004). Interestingly, we found that the protective effect attributed to the HFN1B locus could be mediated by the SULT1A1 protein (p = 0.00030), an arylsulfotransferase that catalyzes the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. In addition to these results, eQTL analysis revealed that the HNF1Brs7501939, HNF1Brs757210, HNF1Brs4430796, NOTCH2rs10923931, and RBMS1rs7593730 SNPs influence the risk of PCa through the modulation of mRNA levels of their respective genes in whole blood and/or liver. These results confirm that functional TD2-related variants influence the risk of developing PCa, but also highlight the need of additional experiments to validate our functional results in a tumoral tissue context.

Follow-Up Biomarkers in the Evolution of Prostate Cancer, Levels of S100A4 as a Detector in Plasma.

The management and screening of prostate cancer (PC) is still the main problem in clinical practice. In this study, we investigated the role of aggressiveness genetic markers for PC stratification. We analyzed 201 plasma samples from PC patients and controls by digital PCR. For selection and validation, 26 formalin-fixed paraffin-embedded tissues, 12 fresh tissues, and 24 plasma samples were characterized by RNA-Seq, immunochemistry, immunofluorescence, Western blot, and extracellular-vesicles analyses. We identified three novel non-invasive biomarkers; all with an increased expression pattern in patients (PCA3: p = 0.002, S100A4: p ≤ 0.0001 and MRC2: p = 0.005). S100A4 presents the most informative AUC (area under the curve) (0.735). Combination of S100A4, MRC2, and PCA3 increases the discriminatory power between patients and controls and between different more and less aggressive stages (AUC = 0.761, p ≤ 0.0001). However, although a sensitivity of 97.47% in PCA3 and a specificity of 90.32% in S100A4 was reached, the detection signal level could be variable in some analyses owing to tumor heterogeneity. This is the first time that the role of S100A4 and MRC2 has been described in PC aggressiveness. Moreover, the combination of S100A4, MRC2, and PCA3 has never been described as a non-invasive biomarker for PC screening and aggressiveness.

Identification of MicroRNAs as Viable Aggressiveness Biomarkers for Prostate Cancer.

MiRNAs play a relevant role in PC (prostate cancer) by the regulation in the expression of several pathways' AR (androgen receptor), cellular cycle, apoptosis, MET (mesenchymal epithelium transition), or metastasis. Here, we report the role of several miRNAs' expression patterns, such as miR-93-5p, miR-23c, miR-210-3p, miR-221-3p, miR-592, miR-141, miR-375, and miR-130b, with relevance in processes like cell proliferation and MET. Using Trizol® extraction protocol and TaqMan™ specific probes for amplification, we performed miRNAs' analysis of 159 PC fresh tissues and 60 plasmas from peripheral blood samples. We had clinical data from all samples including PSA, Gleason, TNM, and D'Amico risk. Moreover, a bioinformatic analysis in TCGA (The Cancer Genome Atlas) was included to analyze the effect of the most relevant miRNAs according to aggressiveness in an extensive cohort (n = 531). We found that miR-210-3p, miR-23c, miR-592, and miR-93-5p are the most suitable biomarkers for PC aggressiveness and diagnosis, respectively. In fact, according with our results, miR-93-5p seems the most promising non-invasive biomarker for PC. To sum up, miR-210-3p, miR-23c, miR-592, and miR-93-5p miRNAs are suggested to be potential biomarkers for PC risk stratification that could be included in non-invasive strategies such as liquid biopsy in precision medicine for PC management.

Influence of Oxidative Stress-Related Genes on Susceptibility to Fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a complex syndrome to diagnose and treat because of its unknown etiology. However, previous studies reported that patients with FM experience oxidative stress. OBJECTIVES: In this study, we investigated single-nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in oxidative stress (superoxide dismutase 1 [SOD1], catalase, and NADPH oxidase [CYBA]) in patients with FM and in healthy subjects, as well as the possible relation with demographic and clinical manifestations of FM. METHODS: A total of 141 patients with FM and 73 healthy subjects participated in this case-control study. For DNA extraction, buccal swabs were collected from patients with FM, and a peripheral blood sample was extracted from controls. We analyzed SNPs in genes related to oxidative stress (rs10432782 in SOD1, rs1001179 in catalase, and rs4673 in CYBA) using TaqMan probes. In patients with FM, severity of FM, fatigue, and pain were assessed by Fibromyalgia Impact Questionnaire, Multidimensional Fatigue Inventory, and Visual Analogue Scale (VAS), respectively. Physical (PCS-12) and mental (MCS-12) health statuses were evaluated by the 12-Item Short-Form Health Survey. RESULTS: The selected SNPs did not show significant differences between patients with FM and controls. The rs10432782 (SOD1) was associated with Fibromyalgia Impact Questionnaire scores in patients with FM, whereas the rs4673 (CYBA) was associated with the Multidimensional Fatigue Inventory score, MCS-12 score, and duration of the disease. DISCUSSION: We have identified significant correlations between SOD1 and CYBA variants with clinical manifestations of FM. These results provide new insights into the pathogenesis of FM that could be useful for guiding future studies along the way to find the cause(s) of this syndrome.

Determination of Exosome Mitochondrial DNA as a Biomarker of Renal Cancer Aggressiveness.

Here, the role of non-invasive biomarkers in liquid biopsy was evaluated, mainly in exosomes and mitochondrial DNA (mtDNA) as promising, novel, and stable biomarkers for renal cell carcinoma (RCC). A total of 140 fractions (named from B to F) obtained by ultracentrifugations of whole blood samples from 28 individuals (13 patients and 15 controls) were included. Nanoparticle Tracking Analysis (NTA) was conducted to characterized exosomal fraction. Subsequently, an analysis of digital PCR (dPCR) using the QuantStudio™ 3D Digital PCR platform was performed and the quantification of mtDNA copy number by QuantStudioTM 12K Flex Real-Time PCR System (qPCR) was developed. Moreover, Next Generation Sequencing (NGS) analyses were included using MiSeq system (Illumina, San Diego, CA, USA). An F fraction, which contains all exosome data and all mitochondrial markers, was identified in dPCR and qPCR with statistically significant power (adjusted p values ≤ 0.03) when comparing cases and controls. Moreover, present analysis in mtDNA showed a relevant significance in RCC aggressiveness. To sum up, this is the first time a relation between exosomal mtDNA markers and clinical management of RCC is analyzed. We suggest a promising strategy for future liquid biopsy RCC analysis, although more analysis should be performed prior to application in routine clinical practice.

Post-Surgery Circulating Tumor Cells and AXL Overexpression as New Poor Prognostic Biomarkers in Resected Lung Adenocarcinoma.

BACKGROUND: The prognosis of early stage non-small cell lung cancer (NSCLC) is quite disappointing and the benefits of adjuvant therapy are relatively small. Thus, there is an urgent need to identify novel prognostic and predictive biomarkers. Lung adenocarcinoma has distinct clinical-pathological characteristics and novel therapeutic strategies are under active evaluation in the adjuvant setting. Here, we investigated the prognostic impact of circulating tumor cells (CTCs) and gene and miRNA tissue expression in resectable NSCLC. PATIENTS AND METHODS: We assessed the association between CTC subpopulations and the outcome of resected early stage lung adenocarcinoma (ADC) patients at three different time-points (CTC1-3) (before surgery, after one month, and after six months) in comparison to squamous cell carcinoma (SCC). Furthermore, gene and miRNA tissue expression, immunoprofiling, and epithelial-to-mesenchymal transition (EMT) markers were correlated with outcome. RESULTS: ADC (n = 47) and SCC (n = 50) revealed different tissue expression profiles, resulting in the presence of different CTC subpopulations. In ADC, miR-155 correlated with AXL and IL6R expression, which were related to the presence of EMT CTC1 (p = 0.014 and p = 0.004). In the multivariate analysis, CTC2 was an independent prognostic factor for relapse-free survival, and CTC3 and AXL were independent prognostic for overall survival only in ADC. Neither the surgery nor the adjuvant treatment influenced the prognosis of these patients. CONCLUSIONS: Our study elucidate the prognostic impact of tissue AXL expression and the presence of CTCs after surgery in adenocarcinoma patients. Tissue AXL expression and CTC EMT activation could potentially represent biomarkers for the stratification of ADC patients that might benefit from new adjuvant therapies.

Adherence to Mediterranean diet and risk of prostate cancer.

In Europe, countries following the traditional Mediterranean Diet (MeDi), particularly Southern European countries, have lower prostate cancer (PCa) incidence and mortality compared to other European regions. In the present study, we investigated the association between the MeDi and the relative risk of PCa and tumor aggressiveness in a Spanish population. Among individual score components, it has been found that subjects with PCa were less likely to consume olive oil as the main culinary fat, vegetables, fruits and fish than those without. However, these differences were not statistically significative. A high intake of fruit, vegetables and cooked tomato sauce Mediterranean style (sofrito) was related to less PCa aggressiveness. Results showed that there are no differences in the score of adherence to the Mediterranean dietary patterns between cases and controls, with mean values of 8.37 ± 1.80 and 8.25 ± 2.48, respectively. However, MeDi was associated with lower PCa agressiveness according to Gleason score. Hence, relations between Mediterranean dietary patterns and PCa are still inconclusive and merit further investigations. Further large-scale studies are required to clarify the effect of MeDi on prostate health, in order to establish the role of this diet in the prevention of PCa.

Improving the genetic signature of prostate cancer, the somatic mutations.

BACKGROUND: Somatic mutations have been related to the highest incidence of metastatic disease and different treatment responses. The molecular cause of prostate cancer (PC) is still unclear; however, its progression involves alterations in oncogenes and tumor suppressor genes as well as somatic mutations such as the ones in PIK3CA gene. A high percentage of PC is considered sporadic, which means that the damage to the genes occurs by chance after birth (mainly somatic mutations will drive the cancer event). However, little is known about somatic mutations in PC development. MATERIALS AND METHODS: We evaluated prostate biopsies in the main somatic mutations genes (PIK3CA, TP53, EGFR, KIT, KRAS, PTEN, and BRAF) among individuals with PSA values>4ng/ml (n = 125), including affected and unaffected PC subjects. RESULTS: Mutations in KIT gene are related to aggressive PC: TNM stages II to III, Gleason score ≥ 7 and D'Amico risk (P = 0.037, 0.040, and 0.017). However, there are no statistical significant results when more than 3 somatic mutations are presented in the same individual. In relation to environmental factors (smoking, diet, alcohol intake, or workplace exposure) there are no significant differences in the effect of environmental exposure and the somatic mutation presence. The most prevalent mutations among patients with PC are c.1621A>C (rs3822214) in KIT, c.38G>C (rs112445441) in KRAS and c.733G>A (rs28934575) in TP53 genes. KRAS, KIT, and TP53 genes are the most prevalent ones in patients with PC. CONCLUSIONS: Somatic alterations predisposing to chromosomal rearrangements in PC remain largely undefined. We show that KIT, KRAS, and TP53 genes have a higher presence among patients with PC and that mutations in KIT gene are related to an aggressive PC. However, we did not find any environmental effect in somatic mutations among PC individuals.

Bioactive compounds of the Mediterranean diet and prostate cancer.

OBJECTIVE: The purpose of this review is to examine the evidence on the effects of bioactive constituents of the Mediterranean diet (MeDi) on prostate cancer (PCa) risk. METHODS: The search for articles came from extensive research in the following databases: PubMed, Scopus, and Web of Science. We used the search terms "Mediterranean diet," "lycopene," "vitamin E," "vitamin C," "Selenium," "resveratrol," "prostate cancer," and combinations, such as "lycopene and prostate cancer" or "resveratrol and prostate cancer." RESULTS: Numerous studies investigating the effect of various dietary nutrients on PCa have suggested that selenium is probably the most promising. Several studies reported reduced PCa risk associated with vitamin C and E intake, while other studies reported no association. Lycopene inhibits cell proliferation and inducts apoptosis, thus protecting against cancer. Also, it has been found in various in vivo and in vitro studies that resveratrol, inhibits PCa development. CONCLUSIONS: The high content of bioactive phytochemicals in the MeDi is of particular interest in the prevention of PCa. Further large-scale studies are required to clarify the effect of MeDi bioactive compounds on prostate health, in order to establish the role of this diet in the prevention of PCa.

The influence of nutritional factors on prostate cancer incidence and aggressiveness.

There is an increasing evidence for a link between nutrition, lifestyle and prostate cancer (PCa) development and/or progression of disease. The objective of this study was to examine the association between dietary factors and PCa incidence and aggressiveness in a case-control study. After the analysis of the anatomic pathology, subjects were classified in patients with PCa (n = 157) and controls (n = 158). Clinical data including Gleason score, PSA values and biopsy results, were compiled. Frequencies of food consumption and sociodemographic data were also obtained. The results showed that physical activity was significantly higher in control (p < .022). It was also found that some nutritional habits offer a protective effect among studied subjects, like high nuts (p = .041) and fish (p = .041) intakes. Moreover, there was a significant reduction in risk (p = .029) in cases with a higher fruits and vegetables intakes. A decreased risk of aggressive PCa was associated with fruits, vegetables, legumes and fish intakes. However, these relationships were not statistically significant when data were adjusted for covariates. In conclusion, this study found an inverse association between PCa risk and the intake of fruits and vegetables, fish and nuts. The results suggested that a diet with higher intakes of these foods as Mediterranean diet may lower the risk of PCa in the studied population. As dietary factors are modifiable, identifying food groups or dietary patterns that modulate the risk of PCa and its aggressiveness can offer effective and practical strategies for its primary prevention.

Association between polymorphisms in sex hormones synthesis and metabolism and prostate cancer aggressiveness.

Novel biomarkers for prostate cancer (PCa) diagnosis and prognosis are necessary to improve the accuracy of current ones employed in clinic. We performed a retrospective study between the association of several polymorphisms in the main genes involved in the synthesis and metabolism of sex hormones and PCa risk and aggressiveness. A total of 311 Caucasian men (155 controls and 156 patients) were genotyped for 9 SNPs in AR, CYP17A1, LHCGR, ESR1 and ESR2 genes. Diagnostic PSA serum levels, Gleason score, tumor stage, D´Amico risk and data of clinical progression were obtained for patients at the moment of the diagnosis and after 54 months of follow-up. Chi-squared test were used for comparisons between clinical variables groups, logistic regression for clinical variables associations between SNPs; and Kaplan-Meier for the association between SNPs and time to biochemical progression. We found 5 variants (CYP17A1) rs743572, rs6162, rs6163; (LHCGR) rs2293275 and (ESR2) rs1256049 that were statistically significant according to clinical variables (PSA, D´Amico risk and T stage) on a case-case analysis. Moreover, the presence of A and G alleles in rs743572 and rs6162 respectively, increase the risk of higher PSA levels (>10 ng/µl). With respect to D´Amico risk rs743572 (AG-GG), rs6162 (AG-AA) and rs6163 (AC-AA) were associated with an increased risk; and last, AC and AA genotypes for rs6163 were associated with a shorter biochemical recurrence free survival (BRFS) in patients with radical prostatectomy. In multigene analysis, several variants in SNPs rs2293275, rs6152, rs1062577, rs6162, rs6163, rs1256049 and rs1004467 were described to be associated with a more aggressiveness in patients. However, none of the selected SNPs show significant values between patients and controls. In conclusion, this study identified inherited variants in genes CYP17A1, LHCGR and ESR2 related to more aggressiveness and/or a poor progression of the disease. According to this study, new promise PCa biomarkers for clinical management could be included in these previous SNPs.

Significance of EGFR Expression in Circulating Tumor Cells.

This chapter focuses on a deep description of the epidermal growth factor receptor (EGFR) expression in circulating tumor cells (CTCs) and its main role in cancer progression, genetic changes related to metastasis , and resistance to treatment. The aberrant behavior of cancer cells is caused by genetic mutations and altered patterns of gene expression. These changes can be responsible for an increase in cell motility but also an ability of CTCs to survival in different microenvironments, as well as developing therapy-resistant clones. Finally, CTCs can acquire the ability to invade distant organs, where metastatic foci can develop.

Association between RNASEL, MSR1, and ELAC2 single nucleotide polymorphisms and gene expression in prostate cancer risk.

BACKGROUND: There is contradictory evidence of the effects that environmental factors-dietary habits (ingestion rates of red meat, soy products, fish, etc.) and work environment (exposure to metals, pesticides, several toxic products, etc.)-and KLK3, AR, RNASEL, MSR1, and ELAC2 expression patterns have on prostate cancer (PCa). In our study, we investigated the potential association between KLK3, AR, RNASEL, MSR1, and ELAC2 polymorphisms, expression patterns, exposure to environmental factors, and PCa in a Spanish cohort. Blood and fresh tissue samples were collected from 322 subjects with prostate-specific antigen (PSA)>4ng/ml to determine their genotypes (RNASEL, MSR1, and ELAC2) and assess messenger ribonucleic acid expression levels (by quantitative amplification testing). MAIN FINDINGS: Among clinical parameters, a 63.6% of patients with CC variants in rs11545302 (ELAC2) had PSA>20ng/ml (P = 0.008), and rs486907 (RNASEL), with 52.8% of patients with CT variants with Gleason score>7. Regarding TNM stage, patients with GG variants, rs4792311 (ELAC2) generally had stage 1 tumors. Genetic expression analysis revealed RNASEL (P = 0.007) was underexpressed in PCa tissue, whereas KLK3 (P = 0.041) was overexpressed. As to environmental factors, the intake of dried fruits (P = 0.036) and practice of sports (P = 0.024) revealed an effect in PCa. Moreover, environmental factors were observed to affect gene expression patterns. Thus, RNASEL (P = 0.018) and ELAC2 (P = 0.023) were found to be underexpressed in patients who ate processed foods frequently; MSR1 (P = 0.024) and AR (P = 0.004) were underexpressed in patients who did not practice sports; and KLK3 (P = 0.039; P = 0.046) underexpressed in patients exposed to dust and toxic products. CONCLUSIONS: This is the first study to analyze the correlation between RNASEL, MSR1, and ELAC2 genotypes and messenger ribonucleic acid expression in PCa. RNASEL and KLK3 show different expression patterns in normal vs. tumor tissue, which supports their reported relevance in human cancer. The results obtained confirm that RNASEL plays a crucial role in PCa. Environmental factors such as exercise, exposure to toxic agents, and intake of processed foods are associated with PCa.

Lifestyle and dietary factors in relation to prostate cancer risk.

The aim of the present study was to determine the association between the socio-demographic, lifestyle factors, and dietary habits with the risk of prostate cancer (PC) in a case-control study of Spanish men. None of the socio-demographic, lifestyle or dietetic variables was found predictors of PC risk. Body mass index was associated with an increased risk for aggressive PC and fruit consumption with lower Gleason scores, thus less aggressive cancers. Nonetheless, after applying Bonferroni correction, these variables were not still associated with PC aggressiveness. More adequately, powered epidemiological studies that measure the effect of lifestyle and dietary intake in PC risk and aggressiveness are warranted to further elucidate the role of these modifiable factors on PC etiology.

Prognostic role of genetic biomarkers in clinical progression of prostate cancer.

The aim of this study was to analyze the use of 12 single-nucleotide polymorphisms in genes ELAC2, RNASEL and MSR1 as biomarkers for prostate cancer (PCa) detection and progression, as well as perform a genetic classification of high-risk patients. A cohort of 451 men (235 patients and 216 controls) was studied. We calculated means of regression analysis using clinical values (stage, prostate-specific antigen, Gleason score and progression) in patients and controls at the basal stage and after a follow-up of 72 months. Significantly different allele frequencies between patients and controls were observed for rs1904577 and rs918 (MSR1 gene) and for rs17552022 and rs5030739 (ELAC2). We found evidence of increased risk for PCa in rs486907 and rs2127565 in variants AA and CC, respectively. In addition, rs627928 (TT-GT), rs486907 (AG) and rs3747531 (CG-CC) were associated with low tumor aggressiveness. Some had a weak linkage, such as rs1904577 and rs2127565, rs4792311 and rs17552022, and rs1904577 and rs918. Our study provides the proof-of-principle that some of the genetic variants (such as rs486907, rs627928 and rs2127565) in genes RNASEL, MSR1 and ELAC2 can be used as predictors of aggressiveness and progression of PCa. In the future, clinical use of these biomarkers, in combination with current ones, could potentially reduce the rate of unnecessary biopsies and specific treatments.