Association of MTHFR (C677T, A1298C) and MTRR A66G polymorphisms with fatty acids profile and risk of neural tube defects.

OBJECTIVE: This study aims to determine if 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase reductase (MTRR A66G) gene polymorphisms were associated with fatty acid (FA) levels in mothers of fetuses with neural tube defects (NTDs) and whether these associations were modified by environmental factors. METHODS: Plasma FA composition was assessed using capillary gas chromatography. Concentrations of studied FA were compared between 42 mothers of NTDs fetuses and 30 controls as a function of each polymorphism by the Kruskal-Wallis nonparametric test. RESULTS: In MTHFR gene C677T polymorphism, cases with (CT + TT) genotype had lower monounsaturated FAs (MUFA) and omega-3 polyunsaturated FA (n-3 PUFA) levels, but higher omega-6 polyunsaturated FAs (n-6 PUFA) and omega-6 polyunsaturated FAs: omega-3 polyunsaturated FAs (n-6:n-3) ratio levels. In MTRR gene A66G polymorphism, cases with (AG + GG) genotype had lower MUFA levels, but higher PUFA and n-6 PUFA levels. Controls with (AG + GG) genotype had lower n-6 PUFA levels. In MTHFR gene C677T polymorphism, cases with smoking spouses and (CT + TT) genotype had lower MUFA and n-3 PUFA levels, but higher PUFA, n-6 PUFA, and n-6:n-3 ratio levels. Cases with (CT + TT) genotype and who used sauna during pregnancy had lower n-3 PUFA levels. In MTRR gene A66G polymorphism, cases with (AG + GG) genotype and who used sauna during pregnancy had higher PUFA and n-6 PUFA levels. CONCLUSIONS: Further research is required to clarify the association of FA metabolism and (MTHFR, MTRR) polymorphisms with NTDs.

Circulating miR-16-5p, miR-92a-3p and miR-451a are biomarkers of lung cancer in Tunisian patients.

Lung cancer is one of the most common type of cancer and, despite significant advances in screening and diagnosis approaches, a large proportion of patients at diagnosis still present advanced stages of the disease with distant metastasis and bad prognosis. Finding and validating biomarkers of lung cancer is therefore essential. Such studies are often conducted on European, American and Asian populations and the relevance of these biomarkers in other populations remains less clear. In that prospect, we investigated the expression level of seven microRNAs, chosen from the medical literature (miR-16-5p, miR-92a-3p, miR-103a-3p, miR-375-3p, miR-451a, miR-520-3p and miR-let-7e-5p), in the blood of Tunisian lung cancer patients, treated or not by chemotherapy, and healthy control individuals. We found that high expression levels of circulating miR-16-5p, miR-92a-3p and miR-451a in the plasma of untreated patients discriminate them from healthy control individuals. In addition, miR-16-5p and miR-451a expression levels are significantly reduced in the plasma of chemotherapy-treated patients compared to untreated patients. Our results confirmed previous work in other populations worldwide and provide further evidence that circulating miR-16-5p, miR-92a-3p and miR-451a potentially regulate key pathways involved in the initiation and progression of cancer.

TH17 cells expressing CD146 are significantly increased in patients with Systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disorder characterized by vascular damage, excessive fibrosis and abnormal T cells immune-regulation. CD146 is an adhesion molecule essentially expressed in the vascular system, but also on TH17 lymphocytes. In view of the recently described role of CD146 in SSc, we hypothesized an involvement of CD146 positive TH17 cells in this disease. Compared to healthy controls, we showed that both soluble form of CD146 (sCD146), and IL17A levels were increased in patients with SSc with a positive correlation between both factors. A significant increase in TH17 cells attested by an increase of RORγT, IL17A mRNA and CD4+ IL17A+ cell was observed in patients with SSc. Interestingly, the percentage of TH17 cells expressing CD146 was higher in patients with SSc and inversely correlated with pulmonary fibrosis. In vitro experiments showed an augmentation of the percentage of TH17 cells expressing CD146 after cell treatment with sCD146, suggesting that, in patients the increase of this sub-population could be the consequence of the sCD146 increase in serum. In conclusion, TH17 cells expressing CD146 could represent a new component of the adaptive immune response, opening the way for the generation of new tools for the management of SSc.

Association of MTHFR C677T, MTHFR A1298C, and MTRR A66G Polymorphisms with Neural Tube Defects in Tunisian Parents.

OBJECTIVE: This study aims to investigate the association of 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase reductase (MTRR A66G) gene polymorphisms with neural tube defects (NTDs) in a Tunisian population. METHODS: Genotyping was performed by polymerase chain reaction with restriction fragment length polymorphisms (PCR-RFLPs) using the restriction enzymes. Allele and genotype frequencies were compared between mothers and fathers of fetuses with NTDs with matched controls based on an association analysis using SPSS software. RESULTS: MTHFR (C677T, A1298C) and MTRR A66G polymorphisms were found to be protector factors for NTD fetuses in the mother group. In addition, a combination of the three wild-type alleles C677/A1298/A66 has increased four-fold the incidence of NTDs (p = 0.004, OR = 3.96, 95% CI: 1.53-10.23). In the father group, MTHFR C677T was a risk factor for NTDs. However, no association was found between MTHFR A1298C, MTRR A66G, and the occurrence of this anomaly. The analysis of MTHFR C677T and MTRR A66G polymorphisms has demonstrated a significant difference in vitamin B12 levels between recessive and dominant genotypes in case mothers (p < 0.05). CONCLUSION: Additional studies are required to better understand the roles of parental gene polymorphisms related to folate-homocysteine metabolism in the pathogenesis of NTD.

Neuroprotective effects of curcumin against acetamiprid-induced neurotoxicity and oxidative stress in the developing male rat cerebellum: biochemical, histological, and behavioral changes.

Curcumin is a molecule found in turmeric root that has anti-inflammatory, antioxidant, and anti-tumor properties and has been widely used as both an herbal drug and a food additive to treat or prevent neurodegenerative diseases. This study aimed to investigate the effect of curcumin on neurobehavioral and neuropathological alterations induced by acetamiprid on male rats. Three groups of ten male Wistar rats each were used for the study: the first was a control group (CTR) that did not consume acetamiprid (ACE); the second was an experimental group (ACE) that consumed 40 mg/kg body weight/day of acetamiprid; and the third group (CUR) received curcumin (100 mg/kg) and acetamiprid (40 mg/kg) in combination. Neurobehavioral evaluations including inclined plane performance and forepaw grip time were studied. Treatment with CUR significantly prevented ACE-treated rats from impairments in the performance of neurobehavioral tests, indicating the presence of deficits on sensorimotor and neuromuscular responses. In addition, Curcumin administration protects rats against acetamiprid-induced cerebellum toxicity such as increase in AChE and BChE activities, decrease on cells viability, oxidative stress, and an increase of intracellular calcium. Taken together, these results demonstrate for the first time that ACE treatment substantially impairs the survival of primary neuronal cells through the induction of necrosis concomitantly with the generation of an oxidative stress. Additionally, curcumin reduced histopathological changes caused by ACE.

Maternal 25-hydroxyvitamin D level and the occurrence of neural tube defects in Tunisia.

OBJECTIVE: To determine whether low vitamin D levels in pregnant women are associated with the occurrence of neural tube defects (NTDs) in Tunisia. METHODS: In a prospective study, pregnant women were recruited at a center in Tunis between January 1, 2012, and December 30, 2013. Women carrying a fetus with a severe NTD were recruited before elective termination. Matched, healthy pregnancy women were enrolled into a control group. Plasma levels of 25-hydroxyvitamin D were measured by a competitive chemiluminescence immunoassay. RESULTS: Overall, 68 women formed the NTD group and 64 the control group. The mean maternal vitamin D level was significantly lower in the NTD group (20.65±10.25nmol/L) than in the control group (28.30±13.82nmol/L; P<0.001). Vitamin D deficiency was recorded for 53 (78%) women in the NTD group and 39 (61%) in the control group. Vitamin D insufficiency was recorded for 15 (22%) women in the NTD group and 20 (31%) in the control group. Vitamin D sufficiency was found only in the control group (n=5 [8%]; P<0.001). CONCLUSION: The findings confirm an association between a decreased vitamin D level in pregnant women and the risk of fetal NTDs.

Association of maternal homocysteine and vitamins status with the risk of neural tube defects in Tunisia: A case-control study.

BACKGROUND: This study was conducted to determine whether low folate and vitamin B12 levels, as well as high homocysteine levels in pregnant women are associated with neural tube defects (NTDs) in Tunisia. METHODS: A total of 75 NTDs pregnancies and 75 matched controls were included in the study. Their vitamin B12, folate, and red blood cell folate concentrations were measured using a radio-immunoassay kit and total homocysteine concentrations were determined using a fluorescent polarization immunoassay. RESULTS: Vitamin B12 and folate concentrations were lower in NTD-affected pregnant women than in controls (respectively, p = 0.009 and p < 0.001). Total homocysteine concentration was significantly higher in the NTDs group than in controls (p = 0.008). In the case group, the folate levels were positively related with vitamin B12 levels (r = 0.54; p < 0.001) and negatively correlated with total homocysteine levels (r = -0.19; p = 0.04). Besides, red blood cell folate levels were positively correlated with folate levels (r = 0.24; p = 0.02) and negatively correlated with total homocysteine levels (r = -0.37; p = 0.001). CONCLUSION: Lower concentrations of folate and vitamin B12 are related to the increased risk of NTDs. Both folate and vitamin B12 intake insufficiency could contribute to the increased risk of NTDs. A dietary supplement, combining folate and vitamin B12, might be an effective measure to decrease the NTDs incidence in Tunisia.

Breast cancer in Tunisia: association of body mass index with histopathological aspects of tumors.

BACKGROUND: Previous studies have suggested a link between obesity and breast cancer (BC). However, there is no universal consensus, especially in population based studies. Because only few studies have been conducted on African women, we aimed here to assess the relationship between BMI at time of diagnosis and the BC histopathological features among Tunisian patients according to menopausal status using a hospital-based prospective cohort study. MATERIALS AND METHODS: Clinical and pathological data were collected from 262 patients stratified on four groups according to their BMI. The relationship between BMI and histopathological features at diagnosis was analysed using univariate and multivariate analysis. Receiver-operating characteristic (ROC) curves were used to evaluate the performance of BMI in predicting of high tumor grade, in comparison to ki-67 index of proliferation. RESULTS: Obesity was correlated with larger tumors, advanced grade and with ER-PR- Her2+ BC subtype. An association of BMI with tumor size and tumor grade was observed in both premenopausal and postmenopausal women. Additionally, a significant association between BMI and ER+, ER+PR+Her2+ and ER-PR-Her2+ status was revealed for premenopausal patients, while only ER+PR+Her2+ was associated with BMI for postmenopausal women. Finally, our results showed that compared to Ki67 proliferation index, BMI is a useful prognostic marker of high grade BC tumors. CONCLUSIONS: These data are the first to show that in Tunisia obese women suffering from BC have significantly larger tumors and advanced tumor grade and that higher BMI might influence tumor characteristics and behavior.

MicroRNAs 146a and 147b biomarkers for colorectal tumor's localization.

The recently identified class of microRNAs (miRs) provided a new insight into cancer research, since abnormalities of members of microRNAs family have been found in various types of cancer. However, the relationship between five miRNAs (miR146a, miR155, miR21, miR135a, and miR147b) and colorectal cancer remains unclear. In the present study, we examined expression of these miRNAs in 25 pair-matched colon cancer tissues and normal colon mucosa. The expression levels of miR146a, miR155, miR21, miR135a, and miR147b were quantified by real-time PCR. We found that miR21, miR146a, and miR135a were all expressed at higher levels in colon tumors. On the other hand, miR146a and miR147b expressions are significantly higher in left colon compared to right colon. These two miRs, especially miR146a, seemed to be markers for the left colon tumors. Moreover, significant proportional and inverse correlations were found between miR expressions in tumor and healthy tissue, and the correlations profiles were different depending on cancer localization. Taken together, these results lead us to suggest the presence of different mechanisms regulating miRs expression and consequently their target genes in left and right colon. So the pathway of colorectal carcinogenesis would be different according to the site of the tumor.

Obesity and renal cancer: Role of adipokines in the tumor-immune system conflict.

Epidemiological studies link obesity, as measured by increased body mass index (BMI) to the incidence of renal cell carcinoma (RCC) as well as to the cancer-related mortality of RCC patients. RCC is the third cancer most robustly associated with increased BMI. Understanding the role of the adipose tissue in renal carcinogenesis is therefore of major importance for the development of novel paradigms of RCC prevention and treatment. Here, we discuss the current knowledge on the impact of obesity on the development and progression of RCC as well as the role of adipose tissue-derived hormones (adipokines) in the conflict between growing tumors and the immune system.

Significant association between interleukin-17A polymorphism and colorectal cancer.

Interleukin (IL) 17A is an inflammatory cytokine expressed by Th 17 cells and plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. We have investigated the association between colorectal cancer and polymorphisms of IL17A (rs2275913. G197A). The study was performed in 241 subjects (102 with colorectal cancer and 139 healthy controls). Genotypes were determined by fluorescent-based restriction fragment length polymorphism method. The association between the molecular features at the gene in relation to tumor and patient clinical characteristics was analyzed. There was a significant difference between the genotype frequencies of IL17A G197A of control subjects (GG 68.34 % and GA + AA 31.65 %) and patients with colorectal cancer (GG 47.05 % and GA + AA 52.94 %) (p = 0.001 with odds ratio (OR) 2.45 (1.43-4.11)). IL17A G197A polymorphism is particularly associated with colon cancer. Indeed, the IL17A GG genotype could be considered as a protective factor against colon cancer (p = 0.00001) with OR 3.77 (2.04-6.99). We have noted a significant association of IL17A G197A polymorphism not only with tumor localization (p = 0.003) but also with tumor differentiation (p = 0.0005) in CRC patients. We have also showed a significant association of G197A variant with an increased risk of advanced stage (p = 0.005). Our result suggests that the A allele of IL17A gene is involved in susceptibility to colorectal cancer and is associated with clinical features as tumor location, tumor differentiation, and TNM stage. IL17A polymorphism may serve as biomarker of disease location and progression.

3020insC NOD2/CARD15 polymorphism associated with treatment of colorectal cancer.

Chronic inflammation is closely linked to cancer. The risk of damage by colorectal cancer (CRC) may increase due to autoimmune disease and cryptogenic inflammation. Therefore, genetic factors implicated in the chronic irritation in inflammatory bowel disease such as NOD2/CARD15 may predispose to CRC. In this report, we shed the light on the possible contribution of the NOD2 3020insC variant to CRC risk in a series of 246 Tunisian subjects including 101 patients with CRC and 145 healthy controls. NOD2/CARD15 polymorphism was genotyped by sizing fluorescently labeled PCR products and automated sequencers. We analyzed the association between the molecular features at this gene in relation to tumor and patient characteristics and treatments. Through this qualitative analysis, we found that CRC patients with mutant allele of NOD2/CARD15 were suffering from Crohn's disease (CD) with canonic presentation. We also observed a positive association between 3020insC polymorphism and surgery and chemotherapy. We suppose that around 3% of colorectal cases which happen at an age older than 50 years are associated with the canonic form of CD along with the 3020insC mutation and that these patients are in need for chemotherapy.

Significant association between IL23R and IL17F polymorphisms and clinical features of colorectal cancer.

Th17cells are involved in inflammatory and autoimmune diseases. These cells may be involved in pathological processes mainly producing pro-inflammatory cytokines. Recently, it was shown that the IL23/IL17 pathway plays an important role in the development of inflammatory bowel disease. In general, genes encoding cytokines are genetically polymorphic and polymorphisms in genes IL23R el IL17F were shown associated with susceptibility to Crohn's disease and ulcerative colitis which in their turn are considered as risk factors for developing colorectal cancer (CRC). Our approach is to study IL17F and IL23R polymorphisms as risk factor associated with CRC in the Tunisian population in patients and healthy controls. Interesting, we noted a significant association between IL17F and IL23R polymorphisms and tumor location (p=0.0001 and p=0.049, respectively), tumor histology (p=0.007 and p=0.049, respectively) and tumor architecture (p=0.0000000001 and p=0.07, respectively) in CRC patients. We also showed a significant association of IL17F variant with an increased risk of TNM stage III/IV (p=0.007), showing an increased risk of advanced stage. Finally, we observed a positive link between IL17F polymorphism and CRC patients with lymph nodes (p=0.0000000001) and metastasis (p=0.00000009). However, we found no evidence to support a significant association between IL17F and IL23R polymorphisms and colorectal cancer susceptibility. Our findings suggest that IL17F and IL23R polymorphisms were significantly associated with clinical features variables. The IL17F cytokine appear to be involved in the control of tumor growth and invasion of gastrointestinal tumors. IL17 and IL23 polymorphisms or those of their receptors as important determinants of susceptibility to colorectal cancer are still subject to questioning.

Positive link between variant Toll-like receptor 4 (Asp299Gly and Thr399Ile) and colorectal cancer patients with advanced stage and lymph node metastasis.

Toll-like receptors (TLRs) are considered as major endotoxin-signaling receptor and as crucial sensors of innate immunity. TLRs recognize pathogen-associated molecular patterns; induce effectors genes involving inflammatory cytokines and therefore initiation of adaptative immune responses against pathogens. Recently, it has been shown that TLRs are involved in tumor progression. In fact, increased level of TLR4 is associated with progression of colon malignancies. Even, TLR4 polymorphism has been shown associated with susceptibility to have colorectal cancer. Our study aimed to investigate an association between TLR4 Asp299Gly (D299G) and Thr399Ile (T399I) polymorphisms in Tunisian patients with colorectal cancer. Using a primer extension method (SNaPshot), we genotyped two variants of TLR4 D299G and T399I in 100 patients with colorectal cancer and 140 healthy controls in Tunisian population. Interesting, we noted a significant association between T399I polymorphism and tumor differentiation (p = 0.027) and tumor architecture (p = 0.02) in colorectal cancer (CRC) patients. We also showed a significant association of D299G with an increased risk of advanced stage (p = 0.03). Finally, we observed a positive link between D299G and T399I polymorphisms and CRC patients with lymph node (p = 0.00024; p = 0.0005, respectively) and metastasis (p = 0.001; p = 0.002, respectively). However, we found no evidence to support a significant association between TLR4 D299G and T399I polymorphisms and colorectal cancer susceptibility. Our findings suggest that TLR4 D299G and T399I polymorphisms are significantly associated with clinical features variables. TLR4 polymorphisms may serve as biomarker of disease progression. Therefore, our results need confirmation in even larger studies.

miRNAs in Sera of Tunisian patients discriminate between inflammatory breast cancer and non-inflammatory breast cancer.

In recent years, circulating miRNAs have attracted interest as stable, non-invasive biomarkers for various pathological conditions. Here, we investigated their potential to serve as minimally invasive, early detection markers for inflammatory breast cancer (IBC) and non-inflammatory breast cancer (non-IBC) in serum. miRNA profiling was performed on serum from 20 patients with non-IBC, 20 with IBC, and 20 normal control subjects. Real-time reverse transcription-polymerase chain reaction (qRT-PCR) was applied to measure the level of 12 candidate miRNAs previously identified in other research(miR-342-5p, miR-342--3p, miR-320, miR-30b, miR-29a, miR-24, miR-15a, miR-548d-5p, miR-486-3p, miR-451, miR-337-5p, miR-335).We found that 4 miRNAs (miR-24, miR-342-3p, miR-337-5p and miR-451) were differentially expressed in serum of IBC patients compared to non-IBC, and 3 miRNAs (miR-337-5p ,miR-451and miR-30b) were differentially expressed in IBC and non-IBC patients combined compared to healthy controls. miR-24, miR-342-3p, miR-337-5p and miR-451 were found to be significantly down-regulated in IBC patients compared to non-IBC. Likewise, the expression level of mir-451 showed significant down-regulation in IBC serum, while mir-30b and miR-337-5p were up-regulated in non-IBC serum comparatively to normal controls. Using receiver operational curve (ROC) analysis, we show that dysregulated miRNAs can discriminate patients with IBC and non-IBC from healthy controls with sensitivity ranging from 76 to 81% and specificity from 66 to 80%, for three separate miRNAs. In conclusion, our data suggest that circulating miRNAs are potential biomarkers for classifying IBC and non-IBC, and may also be candidates for early detection of breast cancer.

CD99 and HLA-II immunostaining in breast cancer tissue and their correlation with lymph node metastasis.

In an attempt to better unfold the antitumor immune response and invasion strategies perused by tumor cells, markers such as CD99 and HLA-II have been stained in breast tumors, some of them turned out to be important for prognosis and its outcome. CD99 is involved in the intracellular transport of HLA-II proteins. The expression of HLA-II and CD99 molecules has been demonstrated in a broader range of neoplastic tissues, including some epithelial tumors. In the present work, we stained CD99 and HLA-II in breast malignant and non-malignant tissues sections obtained from biopsies resected surgically from 80 Tunisian women. Data implied that CD99 marks malignant tissue significantly as compared to non-malignant breast tissue. HLA-II staining allowed determining the correlation between breast cancer and HLA-II with cytoplasmic localization. CD99 and HLA-II immunostaining was also examined in correlation with two of the most important breast cancer prognostication in routine clinical practice, the lymph node stage and the histological assessment. Results let suggest that CD99(+)HLA-II(-) is a marker of worst prognostic since this phenotype is strongly linked to lymph node metastasis in breast cancer.

NY-ESO-1 expression and immunogenicity in prostate cancer patients.

BACKGROUND: Prostate cancer is the second leading cause of men cancer-related death. Cancer immunotherapy has been investigated as a treatment which might be instituted at the point of detection of androgen-independent metastatic disease. AIM: to investigate the expression and humoral response against NYESO-1 in patients with prostate cancer (PC) and to analyze the relationship between expression of NY-ESO-1 and clinicopathological features. METHODS: NY-ESO-1 mRNA in surgically resected PC and benign prostatic hyperplasia (BPH) were examined by reverse transcriptionpolymerase chain reaction. The antibody response to NY-ESO-1 was examined by enzyme-linked Elisa assay using recombinant NYESO-1 protein. RESULTS: NY-ESO-1 mRNA was detected in 9 of 23 (39%) PC patients. Antibodies against NY-ESO-1 protein were detected in 12 of 23 (52%) sera of PC patients and in 5 of 9 (55%) of NY-ESO-1 expressing tumors. However, no mRNA copy or NY-ESO-1 antibodies were detected in all BPH patients tested. CONCLUSION: The present study has demonstrated the expression of NY-ESO-1mRNA in prostate Cancer patients and NY-ESO-1 antibody production. Our data suggest that NY-ESO-1 could be used as a tumor marker and constitute a good candidate for vaccine-based immunotherapy for hormonal resistant prostate cancer patients.

Smoking and polymorphisms in xenobiotic metabolism and DNA repair genes are additive risk factors affecting bladder cancer in Northern Tunisia.

Cancer epidemiology has undergone marked development since the nineteen-fifties. One of the most spectacular and specific contributions was the demonstration of the massive effect of smoking and genetic polymorphisms on the occurrence of bladder cancer. The tobacco carcinogens are metabolized by various xenobiotic metabolizing enzymes, such as the super-families of N-acetyltransferases (NAT) and glutathione S-transferases (GST). DNA repair is essential to an individual's ability to respond to damage caused by tobacco carcinogens. Alterations in DNA repair genes may affect cancer risk by influencing individual susceptibility to this environmental exposure. Polymorphisms in NAT2, GST and DNA repair genes alter the ability of these enzymes to metabolize carcinogens or to repair alterations caused by this process. We have conducted a case-control study to assess the role of smoking, slow NAT2 variants, GSTM1 and GSTT1 null, and XPC, XPD, XPG nucleotide excision-repair (NER) genotypes in bladder cancer development in North Tunisia. Taken alone, each gene unless NAT2 did not appear to be a factor affecting bladder cancer susceptibility. For the NAT2 slow acetylator genotypes, the NAT2*5/*7 diplotype was found to have a 7-fold increased risk to develop bladder cancer (OR = 7.14; 95% CI: 1.30-51.41). However, in tobacco consumers, we have shown that Null GSTM1, Wild GSTT1, Slow NAT2, XPC (CC) and XPG (CC) are genetic risk factors for the disease. When combined together in susceptible individuals compared to protected individuals these risk factors give an elevated OR (OR = 61). So, we have shown a strong cumulative effect of tobacco and different combinations of studied genetic risk factors which lead to a great susceptibility to bladder cancer.

The effect of tobacco, XPC, ERCC2 and ERCC5 genetic variants in bladder cancer development.

BACKGROUND: In this work, we have conducted a case-control study in order to assess the effect of tobacco and three genetic polymorphisms in XPC, ERCC2 and ERCC5 genes (rs2228001, rs13181 and rs17655) in bladder cancer development in Tunisia. We have also tried to evaluate whether these variants affect the bladder tumor stage and grade. METHODS: The patients group was constituted of 193 newly diagnosed cases of bladder tumors. The controls group was constituted of non-related healthy subjects. The rs2228001, rs13181 and rs17655 polymorphisms were genotyped using a polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: Our data have reported that non smoker and light smoker patients (1-19PY) are protected against bladder cancer development. Moreover, light smokers have less risk for developing advanced tumors stage. When we investigated the effect of genetic polymorphisms in bladder cancer development we have found that ERCC2 and ERCC5 variants were not implicated in the bladder cancer occurrence. However, the mutated homozygous genotype for XPC gene was associated with 2.09-fold increased risk of developing bladder cancer compared to the control carrying the wild genotype (p = 0.03, OR = 2.09, CI 95% 1.09-3.99). Finally, we have found that the XPC, ERCC2 and ERCC5 variants don't affect the tumors stage and grade. CONCLUSION: These results suggest that the mutated homozygous genotype for XPC gene was associated with increased risk of developing bladder. However we have found no association between rs2228001, rs13181 and rs17655 polymorphisms and tumors stage and grade.

Smoking and polymorphisms in folate metabolizing genes and their effects on the histological stage and grade for bladder tumors.

Folates are the common sources of DNA synthesis and methylation. Cigarette smoking and genetic susceptibility of folate enzymes are two suspected factors most closely associated with bladder cancer development. This study sought to determine the effect of smoking and genetic polymorphisms in folate metabolizing enzymes on the histological stage and grade of bladder tumors in Tunisian patients. A total of 130 patients with urothelial cell carcinomas were examined with respect to smoking status, MTHFR (5,10-methylenetetrahydrofolate reductase), MTR (methionine synthase), MTRR (methionine synthase reductase) and TYMS (thymidylate synthase) genotypes distribution. Our data have reported that tobacco, MTHFR, MTR and MTRR genotypes were not associated with bladder tumor stage. Only TYMS 3R*G/3R*C genotype was associated with increased risk of developing invasive tumors compared to reference group (RR = 1.74; 95% CI: 0.97-3.12). When we studied the superficial bladder tumor group, we have shown a significant statistical differences for the TYMS 3R*G/2R genotype. This genotype presented a 1.68-fold increased risk of developing high grade tumors compared to reference group (RR = 1.68; 95% CI: 1.12-2.54). Moreover, we have shown that patients having at least one copy of 2R allele were at 4.23-fold increased risk for developing high grade tumors compared to reference group (P = 0.022).