Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing.

Adult neurotoxicity (ANT) and developmental neurotoxicity (DNT) assessments aim to understand the adverse effects and underlying mechanisms of toxicants on the human nervous system. In recent years, there has been an increasing focus on the so-called new approach methodologies (NAMs). The Organization for Economic Co-operation and Development (OECD), together with European and American regulatory agencies, promote the use of validated alternative test systems, but to date, guidelines for regulatory DNT and ANT assessment rely primarily on classical animal testing. Alternative methods include both non-animal approaches and test systems on non-vertebrates (e.g., nematodes) or non-mammals (e.g., fish). Therefore, this review summarizes the recent advances of NAMs focusing on ANT and DNT and highlights the potential and current critical issues for the full implementation of these methods in the future. The status of the DNT in vitro battery (DNT IVB) is also reviewed as a first step of NAMs for the assessment of neurotoxicity in the regulatory context. Critical issues such as (i) the need for test batteries and method integration (from in silico and in vitro to in vivo alternatives, e.g., zebrafish, C. elegans) requiring interdisciplinarity to manage complexity, (ii) interlaboratory transferability, and (iii) the urgent need for method validation are discussed.

Biomarkers of Depression among Adolescent Girls: BDNF and Epigenetics.

Alterations in brain-derived neurotrophic factor (BDNF) expression have been suggested to mediate the influence of environmental factors on the emergence of depression through epigenetic modifications. However, research on this subject in the developmental population is lacking and the pathophysiology of adolescent depression remains unclear. We aimed to investigate the alterations in BDNF expression and global DNA methylation in depression among adolescent girls. Thirty female inpatients with the initial diagnosis of depression were assessed before and after the period of antidepressant treatment and compared with thirty age-matched healthy controls. The assessment involved BDNF and proBDNF serum levels, the BDNF gene exon IV promoter methylation, and global DNA methylation. The methylation level in the BDNF gene exon IV promoter was significantly lower in the studied group compared with the control and correlated negatively with the severity of depression. The test distinguished the studied group from the controls with a sensitivity of 37% and specificity of 90%. The differences were no longer present after the period of antidepressant treatment. No differences in the global DNA methylation, BDNF, and proBDNF levels were found. We concluded that decreased methylation in the BDNF exon IV promoter could be considered as a biomarker of a depression state among adolescent girls.

Disruptions of Circadian Genes in Cutaneous Melanoma-An In Silico Analysis of Transcriptome Databases.

Circadian genes are a set of genes that regulate the body's internal clock and influence various physiological processes, including sleep-wake cycles, metabolism and immune function. Skin cutaneous melanoma (SKCM) is a type of skin cancer that arises from the pigment-producing cells in the skin and is the most deadly form of skin cancer. This study has investigated the relevance of circadian gene expression and immune infiltrations in the outcomes of cutaneous melanoma patients. In the present study, in silico methods based on the GEPIa, TIMER 2.0 and cBioPortal databases were performed, so as to investigate the transcript level and prognostic value of 24 circadian genes in SKCM and their relationship with the immune infiltration level. The in silico analysis showed that significantly more than half of the investigated circadian genes have an altered transcript pattern in cutaneous melanoma compared to normal skin. The mRNA levels of TIMELES and BHLHE41 were upregulated, whereas those of NFIL3, BMAL1, HLF, TEF, RORA, RORC, NR1D1, PER1, PER2, PER3, CRY2 and BHLHE40 were downregulated. The presented research shows that SKCM patients with at least one alteration of their circadian genes have decreased overall survival. Additionally, majority of the circadian genes are significantly corelated with the immune cells' infiltration level. The strongest correlation was found for neutrophils and was followed by circadian genes: NR1D2 r = 0.52 p < 0.0001, BMAL1 r = 0.509 p < 0.0001; CLOCK r = 0.45 p < 0.0001; CSNKA1A1 r = 0.45 p < 0.0001; RORA r = 0.44 p < 0.0001. The infiltration level of immune cells in skin tumors has been associated with patient prognosis and treatment response. Circadian regulation of immune cell infiltration may further contribute to these prognostic and predictive markers. Examining the correlation between circadian rhythm and immune cell infiltration can provide valuable insights into disease progression and guide personalized treatment decisions.

Genetic contributions of MHC class I antigen processing and presentation pathway to bladder cancer risk and recurrence.

Human leukocyte antigen class I (HLA class I) antigen processing and presentation pathway (APP) defines anti-tumor immune response. ERAP, TAP, tapasin (TAPBP), and IFNγ modulate APP: control HLA class I expression in the tumor and the repertoire of presented tumor antigens. At the same time, vascular endothelial growth factor (VEGF) acts as an immunomodulator in the tumor microenvironment. The objective of the current study was to examine the association of single nucleotide polymorphisms (SNPs) in the ERAP1, ERAP2, TAP1, TAP2, TAPBP, IFNG genes with the corresponding mRNA expression in bladder cancer (BC) risk and recurrence after transurethral resection of BC. Moreover, we assessed the relationship between HLA class I and VEGF plasma levels and BC recurrence. We analyzed 9 SNPs in 124 BC patients using TaqMan genotyping and compared them with the data from 503 healthy individuals from the 1000 Genomes Project. In addition, we quantified the effects of SNPs on the corresponding mRNA expression in tumor and non-tumor adjacent tissue in 60 BC patients with primary and 30 with recurrent tumor by quantitative real-time PCR. Furthermore, the plasma HLA class I and VEGF levels were analyzed in BC patients and healthy controls by ELISA. IFNG (rs1861493) was associated with BC risk, TAPBP (rs3106189, rs2071888) with recurrence-free survival (RFS). Moreover, TAPBP mRNA expression was lower in tumors than in the adjacent tissue. The SNPs ERAP2 (rs251339) and TAP2 (rs241447, rs241448) variants affected mRNA expression in BC tissue. In tumor tissue, the high mRNA expression of ERAP1 was more common in BC patients with single tumors, ERAP2 in non-smokers, and TAP2 mRNA in recurrence. The lower HLA and higher VEGF plasma levels were observed in BC patients compared with healthy controls. We conclude that the genetic elements responsible for MHC class I APP may influence the BC risk, risk of recurrence, and RFS.

Therapeutic Potential of Selenium and Selenium Compounds in Cervical Cancer.

Cervical cancer is a common female cancer. It is strongly associated with human papillomavirus (HPV) infection. However, HPV infection alone is not sufficient to induce cervical cancer because its development is dependent on the coexistence of several factors that enable the virus to overcome the host immune system. These include individual genetic background, environmental factors, or diet, including dietary selenium intake. Selenium is an essential trace element with antiviral properties and has been shown to exert antitumor effects. Surprisingly, the role of selenium in cervical cancer has not been studied as intensively as in other cancers. Here, we have summarized the existing experimental data on selenium and cervical cancer. It may be helpful in evaluating the role of this nutrient in treatment of the mentioned malignancy as well as in planning further studies in this area.

Expression Biomarkers of Pharmacological Treatment Outcomes in Women with Unipolar and Bipolar Depression.

INTRODUCTION: This study aimed to find the expression biomarkers of pharmacological treatment response in a naturalistic hospital setting. Through gene expression profiling, we were able to find differentially-expressed genes (DEGs) in unipolar (UD) and bipolar (BD) depressed women. METHODS: We performed gene expression profiling in hospitalized women with unipolar (n=24) and bipolar depression (n=32) who achieved clinical improvement after pharmacological treatment (without any restriction). To identify DEGs in peripheral blood mononuclear cells (PBMCs), we used the SurePrint G3 Microarray and GeneSpring software. RESULTS: After pharmacological treatment, UD and BD varied in the number of regulated genes and ontological pathways. Also, the pathways of neurogenesis and synaptic transmission were significantly up-regulated. Our research focused on DEGs with a minimum fold change (FC) of more than 2. For both types of depression, 2 up-regulated genes, OPRM1 and CELF4 (p=0.013), were significantly associated with treatment response (defined as a 50% reduction on the Hamilton Depression Rating Scale [HDRS]). We also uncovered the SHANK3 (p=0.001) gene that is unique for UD and found that the RASGRF1 (p=0.010) gene may be a potential specific biomarker of treatment response for BD. CONCLUSION: Based on transcriptomic profiling, we identified potential expression biomarkers of treatment outcomes for UD and BD. We also proved that the Ras-GEF pathway associated with long-term memory, female stress response, and treatment response modulation in animal studies impacts treatment efficacy in patients with BD. Further studies focused on the outlined genes may help provide predictive markers of treatment outcomes in UD and BD.

Glyphosate and AMPA Induce Alterations in Expression of Genes Involved in Chromatin Architecture in Human Peripheral Blood Mononuclear Cells (In Vitro).

We have determined the effect of glyphosate and aminomethylphosphonic acid (AMPA) on expression of genes involved in chromatin architecture in human peripheral blood mononuclear cells (PBMCs). The cells were incubated with glyphosate and AMPA in the concentrations ranging from 0.5 to 100 µM and from 0.5, to 250 µM, respectively. The expression profile of the following genes by quantitative Real-Time PCR was evaluated: Genes involved in the DNA methylation (DNMT1, DNMT3A) and DNA demethylation process (TET3) and those involved in chromatin remodeling: genes involved in the modification of histone methylation (EHMT1, EHMT2) and genes involved in the modification of histone deacetylation (HDAC3, HDAC5). Gene profiling showed that glyphosate changed the expression of DNMT1, DMNT3A, and HDAC3, while AMPA changed the expression of DNMT1 and HDAC3. The results also revealed that glyphosate at lower concentrations than AMPA upregulated the expression of the tested genes. Both compounds studied altered expression of genes, which are characteristic for the regulation of transcriptionally inactive chromatin. However, the unknown activity of many other proteins involved in chromatin structure regulation prevents to carry out an unambiguous evaluation of the effect of tested xenobiotics on the studied process. Undoubtedly, we have observed that glyphosate and AMPA affect epigenetic processes that regulate chromatin architecture.

Epigenetic Changes in Neoplastic Mast Cells and Potential Impact in Mastocytosis.

Systemic mastocytosis (SM) is a hematologic neoplasm with abnormal accumulation of mast cells in various organ systems such as the bone marrow, other visceral organs and skin. So far, only little is known about epigenetic changes contributing to the pathogenesis of SM. In the current article, we provide an overview of epigenetic changes that may occur and be relevant to mastocytosis, including mutations in genes involved in epigenetic processes, such as TET2, DNMT3A and ASXL1, and global and gene-specific methylation patterns in neoplastic cells. Moreover, we discuss methylation-specific pathways and other epigenetic events that may trigger disease progression in mast cell neoplasms. Finally, we discuss epigenetic targets and the effects of epigenetic drugs, such as demethylating agents and BET-targeting drugs, on growth and viability of neoplastic mast cells. The definitive impact of these targets and the efficacy of epigenetic therapies in advanced SM need to be explored in future preclinical studies and clinical trials.

Genetic and Epigenetic Aspects of Atopic Dermatitis.

Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.

Pathogenesis of psoriasis in the "omic" era. Part III. Metabolic disorders, metabolomics, nutrigenomics in psoriasis.

Psoriasis is a systemic disease that is strictly connected with metabolic disorders (insulin resistance, atherogenic dyslipidemia, arterial hypertension, and cardiovascular diseases). It occurs more often in patients with a more severe course of the disease. Obesity is specially an independent risk factor and it is associated with a worse treatment outcome because of the high inflammatory activity of visceral fatty tissue and the production of inflammatory mediators involved in the development of both psoriasis and metabolic disorders. However, in psoriasis the activation of the Th17/IL-17 and the abnormalities in the Th17/Treg balance axis are observed, but this pathomechanism does not fully explain the frequent occurrence of metabolic disorders. Therefore, there is a need to look for better biomarkers in the diagnosis, prognosis and monitoring of concomitant disorders and therapeutic effects in psoriasis. In addition, the education on the use of a proper diet as a prophylaxis for the development of the above disorders is an important element of holistic care for a patient with psoriasis. Diet may affect gene expression due to epigenetic modification which encompasses interactions of environment, nutrition and diseases. Patients with psoriasis should be advised to adopt proper diet and dietician support.

Pathogenesis of psoriasis in the "omic" era. Part II. Genetic, genomic and epigenetic changes in psoriasis.

Psoriasis is a multifactorial disease in which genetic, environmental and epigenetic factors regulating gene expression play a key role. In the "genomic era", genome-wide association studies together with target genotyping platforms performed in different ethnic populations have found more than 50 genetic susceptible markers associated with the risk of psoriasis which have been identified so far. Up till now, the strongest association with the risk of the disease has been proved for HLA-C*06 gene. The majority of other psoriasis risk SNPs are situated near the genes encoding molecules involved in adaptive and innate immunity, and skin barrier function. Many contemporary studies indicate that the epigenetic changes: histone modification, promoter methylations, long non-coding and micro-RNA hyperexpression are considered as factors contributing to psoriasis pathogenesis as they regulate abnormal keratinocyte differentiation and proliferation, aberrant keratinocytes - inflammatory cells communication, neoangiogenesis and chronic inflammation. The circulating miRNAs detected in the blood may become specific markers in the diagnosis, prognosis and response to the treatment of the disease. The inhibition of expression in selected miRNAs may be a new promising therapy option for patients with psoriasis.

Pathogenesis of psoriasis in the "omic" era. Part IV. Epidemiology, genetics, immunopathogenesis, clinical manifestation and treatment of psoriatic arthritis.

Psoriatic arthritis (PsA) is a chronic, progressive, inflammatory arthropathy associated with psoriasis as well as a complex pathogenesis. Genetic and environmental factors trigger the development of the immune-mediated auto-inflammatory response in different sites: skin, bone marrow, entheses and synovial tissues. Studies of the last two decades have changed the view of PsA from a mild, non-progressive arthritis to an inflammatory systemic disease with serious health consequences, not only associated with joint dysfunction, but also with an increased risk of cardiovascular disease and socioeconomic consequences with significantly reduced quality of life. The joint damage starts early in the course of the disease, thus early recognition and treatment with modern biological treatments, which may modify the natural history and slow down progression of this debilitating disease, is essential for the patient long-term outcome.

Pathogenesis of psoriasis in the "omic" era. Part I. Epidemiology, clinical manifestation, immunological and neuroendocrine disturbances.

Psoriasis is a common, chronic, inflammatory, immune-mediated skin disease affecting about 2% of the world's population. According to current knowledge, psoriasis is a complex disease that involves various genes and environmental factors, such as stress, injuries, infections and certain medications. The chronic inflammation of psoriasis lesions develops upon epidermal infiltration, activation, and expansion of type 1 and type 17 Th cells. Despite the enormous progress in understanding the mechanisms that cause psoriasis, the target cells and antigens that drive pathogenic T cell responses in psoriatic lesions are still unproven and the autoimmune basis of psoriasis still remains hypothetical. However, since the identification of the Th17 cell subset, the IL-23/Th17 immune axis has been considered a key driver of psoriatic inflammation, which has led to the development of biologic agents that target crucial elements of this pathway. Here we present the current understanding of various aspects in psoriasis pathogenesis.

Circadian Gene Polymorphisms Associated with Breast Cancer Susceptibility.

Breast cancer (BC) is a major problem for civilization, manifested by continuously increasing morbidity and mortality among women worldwide. Core circadian genes may play an important role in cancer development and progression. To evaluate the effects of single nucleotide polymorphism (SNP) in circadian genes in BC risk, 16 functional SNPs were genotyped in 321 BC patients and 364 healthy women using the TaqMan fluorescence-labelled probes or High-Resolution Melt Curve technique in the Real-Time PCR system. The selected SNPs were analyzed for the risk of BC, progression, and the influence on gene expression in BC tissue pairs to demonstrate the functionality of genetic variants. The study showed a relationship between an increased BC risk under the dominant genetic model of CRY2 rs10838524, PER2 rs934945, and recessive genetic model of PER1 rs2735611. A protective effect of BMAL1 rs2279287 was observed among carriers with at least one variant allele. Moreover, we found an increased risk of estrogen-/progesterone-positive tumors under the dominant genetic model of PER2 rs934945 and estrogen negative tumors under the variant genotype of CRY2 rs10838524, PER1 rs2735611. We demonstrated significantly altered gene expression of BMAL1, CRY2, PER1, PER2, PER3 according to particular genotypes in the BC tissue pairs. Our findings support the hypothesized role of circadian genes in breast carcinogenesis and indicate probable biomarkers for breast cancer susceptibility.

Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis - Current Status.

Circadian rhythm alterations resulting in disturbed sleep and disturbed melatonin secretion are flagship features of depression. Melatonin, known as a hormone of darkness, is secreted by the pineal gland located near to the center of the brain between the two hemispheres. Melatonin has an antidepressant effect by maintaining the body's circadian rhythm, by regulating the pattern of expression of the clock genes in the suprachiasmatic nucleus (SCN) and modifying the key genes of serotoninergic neurotransmission that are linked with a depressive mood. Melatonin is produced via the metabolism of serotonin in two steps which are catalyzed by serotonin N-acetyltransferase (SNAT) and acetylserotonin-O-methyltransferase (ASMT). Serotonin, SNAT, and ASMT are key melatonin level regulation factors. Melatonin acts mainly on the MT1 and MT2 receptors, which are present in the SCN, to regulate physiological and neuroendocrine functions including circadian entrainment, referred to as a chronobiotic effect. Although melatonin has been known about and refereed to for almost 50 years, the relationship between melatonin and depression is still not clear. In this review, we summarize current knowledge about the genetic and epigenetic regulation of enzymes involved in melatonin synthesis and metabolism as potential features of depression pathophysiology and treatment. Confirmation that melatonin metabolism in peripheral blood partially reflects a disorder in the brain could be a breakthrough in the standardization of measurements of melatonin level for the development of treatment standards, finding new therapeutic targets, and elaborating simple noninvasive clinical tests.

Matrix metalloproteinases and genetic mouse models in cancer research: a mini-review.

Carcinogenesis is a multistep and also a multifactorial process that involves agents like genetic and environmental factors. Matrix metalloproteinases (MMPs) are major proteolytic enzymes which are involved in cancer cell migration, invasion, and metastasis. Genetic variations in genes encoding the MMPs were shown in human studies to influence cancer risk and phenotypic features of a tumor. The complex role of MMPs seems to be important in the mechanism of carcinogenesis, but it is not well recognized. Rodent studies concentrated particularly on the better understanding of the biological functions of the MMPs and their impact on the pathological process, also through the modification of Mmp genes. This review presents current knowledge and the existing evidence on the importance of selected MMPs in genetic mouse models of cancer and human genetic association studies. Further, this work can be useful for scientists studying the role of the genetic impact of MMPs in carcinogenesis.

Lipid peroxidation and glutathione peroxidase activity relationship in breast cancer depends on functional polymorphism of GPX1.

BACKGROUND: Since targeting oxidative stress markers has been recently recognized as a novel therapeutic target in cancer, it is interesting to investigate whether genetic susceptibility may modify oxidative stress response in cancer. The aim of this study was to elucidate whether genetic polymorphism in the antioxidant enzymes is associated with lipid peroxidation in breast cancer. METHODS: We conducted a study among Polish women, including 136 breast cancer cases and 183 healthy controls. The analysis included genetic polymorphisms in five redox related genes: GPX1 (rs1050450), GPX4 (rs713041), SOD2 (rs4880), SEPP1 (rs3877899) and SEP15 (rs5859), lipid peroxidation, the activities of antioxidant enzymes determined in blood compartments as well as plasma concentration of selenium - an antioxidant trace element involved in cancer. Genotyping was performed using the Real Time PCR. Lipid peroxidation was expressed as plasma concentration of thiobarbituric acid reactive substances (TBARS) and measured with the spectrofluorometric method. Glutathione peroxidase activity was spectrophotometrically determined in erythrocytes (GPx1) and plasma (GPx3) by the use of Paglia and Valentine method. Spectrophotometric methods were employed to measure activity of cytosolic superoxide dismutase (SOD1) in erythrocytes (Beauchamp and Fridovich method) and ceruloplasmin (Cp) in plasma (Sunderman and Nomoto method). Plasma selenium concentration was determined using graphite furnace atomic absorption spectrophotometry. RESULTS: Breast cancer risk was significantly associated with GPX1 rs1050450 (Pro198Leu) polymorphism, showing a protective effect of variant (Leu) allele. As compared to the control subjects, lipid peroxidation and GPx1 activity were significantly higher in the breast cancer cases, whereas ceruloplasmin activity was decreased. After genotype stratification, both GPx1 activity and TBARS concentration were the highest in GPX1 Pro/Pro homozygotes affected by breast cancer. At the same time, there was a significant correlation between the level of lipid peroxidation and GPx1 activity among the cancer subjects possessing GPX1 Pro/Pro genotype (r = 0.3043; p = 0.0089), whereas such a correlation was completely absent in the cases carrying at least one GPX1 Leu allele as well as in the controls (regardless of GPX1 genotype). CONCLUSIONS: GPX1 polymorphism may be an important factor modifying oxidative stress response in breast cancer subjects. Further studies are needed to elucidate its potential clinical significance.

Biological monitoring and the influence of genetic polymorphism of As3MT and GSTs on distribution of urinary arsenic species in occupational exposure workers.

PURPOSE: To examine the differences in urinary arsenic metabolism patterns in men affected by occupational exposure, we performed a study on 149 participants­workers of a copper mill and 52 healthy controls without occupational exposure. To elucidate the role of genetic factors in arsenic (As) metabolism, we studied the associations of six polymorphisms: As3MT Met287Thr (T>C) in exon 9; As3MT A>G in 5'UTR; As3MT C>G in intron 6; As3MT T>G in intron 1; GSTP1 Ile105Val and GSTO2 T>C. METHODS: Air samples were collected using individual samplers during work shift. Urine samples were analyzed for total arsenic and arsenic chemical forms (As(III); As(V), MMA, DMA, AsB) using HPLC-ICP-MS. A specific polymerase chain reaction was done for the amplification of exons and flanking regions of As3MT and GSTs. RESULTS: The geometric mean arsenic concentrations in the air were 27.6 ± 4.9 µg/m(3). A significant correlation (p < 0.05) was observed between arsenic in air and sum of iAs +MMA and iAs. As3MT (rs3740400) GG homozygotes showed significantly (p < 0.05) higher %iAs (21.8 ± 2.0) in urine than GC+CC heterozygotes (16.0 ± 2.1). A strong association between the gene variants and As species in urine was observed for GSTO2 (rs156697) polymorphism. CONCLUSIONS: The findings of the study point out that the concentration of iAs or the sum of iAs + MMA in urine can be a reliable biological indicator of occupational exposure to arsenic. This study demonstrates that As3MT and/or GSTs genotype may influence As metabolism. Nevertheless, further studies investigating genetic polymorphism in occupational conditions are required.

Functional polymorphisms in the matrix metalloproteinase genes and their association with bladder cancer risk and recurrence: a mini-review.

Molecular pathogenesis of muscle invasive bladder cancer and non-muscle invasive bladder cancer is incompletely elucidated. It is believed that matrix metalloproteinases, which are involved in the processes of uncontrolled extracellular matrix substrates degradation and participate in modulating the activity of a variety of non-matrix proteins, can contribute to carcinogenesis. Polymorphisms in the MMP genes associated with unique genomic changes in bladder cancer patients are still being investigated to discover direct links with pathophysiological mechanisms. Because of the functional polymorphisms in the MMP genes, which have a proven or likely effect on their protein expression, they could possibly affect the tumor process. The current mini-review synthesizes findings regarding the association of genetic polymorphisms in the MMP genes with bladder cancer risk and recurrence in patients. We discuss the current views on the feasibility of genetic polymorphisms in the MMP1, 2, 3, 7, 8, 9 and 12 genes as a risk, and prognostic markers for patients with bladder cancer. The majority of the research described in the present mini-review proves that the genetic polymorphism in the MMP1 (rs1799750) is the most widely studied, and suggests that the rare genotype, 2G2G, of that gene might show increased susceptibility for bladder cancer, especially among smokers. However, existing statistically significant associations between the genetic polymorphisms in the MMP genes and bladder cancer risk have not been clearly shown, and further studies are necessary in order to positively confirm them or dispel potential false hopes.

Genetic polymorphisms in matrix metalloproteinases (MMPs) and tissue inhibitors of MPs (TIMPs), and bladder cancer susceptibility.

OBJECTIVES: To elucidate genetic polymorphisms of the matrix metalloproteinases (MMPs) MMP1 (rs1799750), MMP2 (rs243865), MMP9 (rs3918242), MMP12 (rs2276109) and tissue inhibitors of MMPs (TIMPs) TIMP1 (rs2070584) and TIMP3 (rs9619311) genes that may be involved in susceptibility to bladder cancer (BC). PATIENTS AND METHODS: We enrolled 241 patients with BC and 199 controls. Genomic DNA samples were extracted from peripheral blood and polymorphisms were analysed by high-resolution melting analysis and by real-time polymerase chain reaction using TaqMan fluorescent probes. RESULTS: Of the six evaluated polymorphisms of MMPs and TIMPs, only one was found to be associated with BC risk. There was a significant difference for MMP1 (rs1799750) 2G/1G+1G/1G genotype (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.39-0.98; P = 0.042). Additionally, there was a joint effect of this genotype on BC risk among 'ever smokers' (OR 0.51, 95% CI 0.28-0.89; P = 0.019), but not in 'never smokers'. The combined genotype MMP2 -1306C/T (rs243865) allele T with MMP9 -1562C/T (rs3918242) allele T was found to increase BC risk (OR 2.00, 95% CI 1.10-3.62; P = 0.022). CONCLUSIONS: Our results suggest that genetic variations in five polymorphisms of MMPs and TIMPs are not associated with a high risk of BC. Only MMP1 polymorphism may be related to the risk of BC, notably in 'ever smokers'. Our study suggests that the effects of polymorphisms of MMPs and TIMPs on BC risk deserve further investigation.