Epithelial-mesenchymal transition dysregulation in prostate cancer: Insights from molecular unraveling and epidemiological analyses in Tunisia, North Africa.

INTRODUCTION: The progression of prostate cancer (PCa) has been linked worldwide, including in African populations, to the dysregulation of the epithelial-mesenchymal transition (EMT). METHODS: To clarify the connection among EMT markers, clinicopathological parameters, and epidemiological factors, we analyzed 35 PCa specimens from patients in Tunisia, a country in North Africa, arranged by stages. We also carried out extensive molecular and epidemiological analyses. RESULTS: Significant dysregulation of EMT genes was found, with an overexpression of ZEB-1, Twist, Snail-1, and Vimentin (p < 0.05) and underexpression of E-cadherin and ß-catenin (p < 0.05). Positive correlations were observed between transcription factors and the mesenchymal marker Vimentin (p < 0.001, r = 0.574; p = 0.029, r = 0.411; and p < 0.001; r = 0.506) according to Spearman correlation analyses, whereas negative correlations were found between epithelial markers (E-cadherin, ß-catenin) and Vimentin (p < 0.05; r < 0). Higher PSA, Gleason scores, and metastasis were all correlated with the dysregulation of EMT (p < 0.05). Notably, there was a positive correlation between higher consumption of tobacco (≥20 Packets per year) and Vimentin expression (p < 0.001, r = 0.854), suggesting a relationship between smoking and EMT activation in the Tunisian population. Moreover, Twist showed a positive correlation with diabetes (p < 0.001, r = 0.385), whereas no significant correlations were found between EMT markers and comorbidities such as hypertension and coronary insufficiency. These results demonstrate the intricate connection between molecular changes, epidemiological factors, and disease progression, and they emphasize the crucial role that EMT plays in promoting PCa aggressiveness in African populations, particularly in Tunisia. CONCLUSION: In summary, understanding these correlations could help develop focused treatment plans and enhance patient outcomes for PCa management in African settings.

An insight into the diagnostic, prognostic, and taxanes resistance of double zinc finger and homeodomain factor's expression in naïve prostate cancer.

Currently, clinical biomarkers are urgently needed to improve patient management to guide personal therapy for cancer. In this study, we investigate the deregulation of Zeb-1 in prostate cancer (PC) Tunisian patients. Expression patterns of the Zeb-1 were investigated in prostate adenocarcinoma and benign prostate biopsies using quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR) and 2-ΔΔCt method. Statistical analysis was used to identify differences across groups depending on gene expression level. Furthermore, we exploited a follow-up over 15 years to correlate Zeb-1 deregulation and clinical outcomes in PC patients. Based on ROC curve analyses, the AUC was found in discriminating PC patients from controls (AUC = 0.757; p < 0.001). In addition, the higher expression level was significantly associated with PSA, Digital Rectal Examination, Gleason score, tumor stage, and distant lymph node metastases. Moreover, Zeb-1 overexpression was correlated with shorter overall survival (OS) (p = 0.042), poor progression-free survival (PFS) (p = 0.007), and with resistance to taxanes (p = 0.012). Our data provide the aberrant expression of Zeb-1 in PC patients suggesting its potential diagnostic, prognostic, and theranostic role. Further functional studies are mandatory to strengthen these results and to uncover the molecular mechanism of this neoplasm. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03941-8.

Co-expression of Twist and Snai1: predictor of poor prognosis and biomarker of treatment resistance in untreated prostate cancer.

BACKGROUND: Prostate cancer (PCa) remains one of the most complex tumors in men. The assessment of gene expression is expected to have a profound impact on cancer diagnosis, prognosis, and treatment decisions. The aim of this study was to determine the utility of the epithelial-mesenchymal transition (EMT) transcription factors Twist and Snai1 in the treatment of naïve prostate cancer. METHODS AND RESULTS: We analyzed formalin-fixed paraffin-embedded (FFPE) prostate tissues from 108 PCa patients and 20 control biopsies using real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and 2-ΔΔCt methods for Twist and Snail gene expression. The expression of Twist and Snai1 mRNA was significantly overexpressed in primary tissues of PCa patients compared with controls using ROC curve. Statistical analysis showed that the mRNAs of these two genes expression Snai1 and Twist were positively correlated with tumor development and prognostic parameters as Gleason score (p < 0.001; r = 0.707) and (p < 0.001; r = 0.627) respectively. The results of Kaplan-Meier analysis showed that mRNA expression of Snai1 and Twist genes expression were significant predictors of poor overall survival (OS) (Log rank p < 0.001) and progression-free survival (PFS) of patients (Log rank p < 0.001). Furthermore, our results showed that the expression of Snai1 and Twist genes expression in primary tissues of PCa patients could predict resistance to androgen deprivation therapy (p < 0.001) and resistance to the acidic drugs abiraterone or enzalutamide (p < 0.001). However, these two transcription factors failed to predict taxanes resistance at the time of diagnosis (p > 0.05). CONCLUSION: These results suggest that Snai1 and Twist are overexpressed during the onset and progression of PCa malignancies and may be theranostic markers of resistance to ADT, abiraterone, or enzalutamide therapy.

Correlation between E-cadherin/ß-catenin, Vimentin expression, clinicopathologic features and drug resistance prediction in naïve prostate cancer: A molecular and clinical study.

Although epithelial-mesenchymal markers play an important role in prostate cancer (PC), further research is needed to better understand their utility in diagnosis, cancer progression prevention, and treatment resistance prediction. Our study included 111 PC patients who underwent transurethral resection, as well as 16 healthy controls. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to examine the expression of E-cadherin, ß-catenin, and Vimentin. We found that E-cadherin and ß-catenin were underexpressed in primary PC tissues. E-cadherin expression was found to be inversely associated with prostate-specific antigen progression (PSA-P; serum marker of progression; p = 0.01; |r| = 0.262). Furthermore, the underexpression of two markers, E-cadherin and ß-catenin, was found to be associated with advanced tumor stage and grade (p < 0.05). On the other hand, Vimentin was overexpressed in PC patients with a fold change of 2.141, and it was associated with the diagnosis, prognosis, and prediction of treatment resistance to androgen deprivation therapy (p = 0.002), abiraterone-acid (p = 0.001), and taxanes (p = 0.029). Moreover, the current study highlighted that poor survival could be significantly found in patients who progressed after primary surgery, did not use drugs, and expressed these genes aberrantly. In Cox regression multivariate analysis (p < 0.05), a positive correlation between the Vimentin marker and coronary heart disease in PC patients was identified (p = 0.034). In summary, the present study highlights the diagnostic (p < 0.001), prognostic (p < 0.001), and therapeutic potential of Vimentin in primary PC (p < 0.05), as well as its implications for cardiovascular disease. Furthermore, we confirm the potential prognostic value of E-cadherin and ß-catenin.

Next-generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment.

Mitochondrial cytopathies, among which the Leigh syndrome (LS), are caused by variants either in the mitochondrial or the nuclear genome, affecting the oxidative phosphorylation process. The aim of the present study consisted in defining the molecular diagnosis of a group of Tunisian patients with LS. Six children, belonging to five Tunisian families, with clinical and imaging presentations suggestive of LS were recruited. Whole mitochondrial DNA and targeted next-generation sequencing of a panel of 281 nuclear genes involved in mitochondrial physiology were performed. Bioinformatic analyses were achieved in order to identify deleterious variations. A single m.10197G>A (p.Ala47Thr) variant was found in the mitochondrial MT-ND3 gene in one patient, while the others were related to autosomal homozygous variants: two c.1412delA (p.Gln471ArgfsTer42) and c.1264A>G (p.Thr422Ala) in SLC19A3, one c.454C>G (p.Pro152Ala) in SLC25A19 and one c.122G>A (p.Gly41Asp) in ETHE1. Our findings demonstrate the usefulness of genomic investigations to improve LS diagnosis in consanguineous populations and further allow for treating the patients harboring variants in SLC19A3 and SLC25A19 that contribute to thiamine transport, by thiamine and biotin supplementation. Considering the Tunisian genetic background, the newly identified variants could be screened in patients with similar clinical presentation in related populations.

An insight into the diagnostic and prognostic value of HOX A13's expression in non-muscle invasive bladder cancer.

BACKGROUND: Several studies have interrogated the molecular pathways and their interacting genes underlying bladder cancer (BCa) tumorigenesis, yet, the role of homeobox genes is still poorly understood. Specifically, HOXA13, which plays an important role as a major actor in the urogenital tract's development. METHODS: Immunohistochemical (IHC) staining was performed to inspect the differential expression of HOXA13 protein in non-muscle-invasive bladder cancer (NMIBC) and non-tumoral tissues. A semiquantitative scoring system was adopted to evaluate the IHC labeling. Correlation to clinical parameters was performed by descriptive statistics. Overall survival was estimated by the Kaplan-Meier method and Cox regression model. The functional HOX A13 protein association networks (PPI) were obtained using String 11.0 database. RESULTS: HOX A13 exhibited cytoplasmic and nuclear staining. Its expression levels were lower in high-grade NMIBC (HG NMIBC) compared to low-grade ones (LG NMIBC). The expression of HOX A13 was correlated to tumor grade (LG/HG) (p = 0.036) and stage (TA/T1) (p = 0.036). Nevertheless, its expression was not correlated to clinical parameters and was not able to predict the overall survival of patients with HG NMIBC. Finally, PPI analysis revealed that HOX A13 seems to be a part of a molecular network holding mainly PBX1, MEIS, ALDH1A2, HOX A10, and HOX A11. CONCLUSION: The deregulation of HOX A13 is not associated with the prognosis of BCa. It seems to be rather implicated in the early initiation of urothelial tumorigenesis and thus may serve as a diagnostic marker in patients with NMIBC. Further experimentations on larger validation sets are mandatory.

Development of a custom next-generation sequencing panel for the determination of bladder cancer risk in a Tunisian cohort.

BACKGOUND: Bladder cancer (BCa) is a heterogeneous disease caused by the interaction between environmental and genetic risk factors. The goal of this case-control study was to evaluate the implication of a selected SNP panel in the risk of BCa development in a Tunisian cohort. We were also interested in studying the interaction between this predictive panel and environmental risk factors. METHODS: The case/control cohort was composed with 249 BCa cases and 255 controls. The designed Bladder cancer hereditary panel (BCHP) was composed of 139 selected variants. These variants were genotyped by an amplification-based targeted Next-Generation Sequencing (NGS) on the Ion Torrent Proton sequencer (Life Technologies, Ion Torrent technology). RESULTS: We have found that rs162555, rs2228000, rs10936599, rs710521, rs3752645, rs804276, rs4639, rs4881400 and rs288980 were significantly associated with decreased risk of bladder cancer. However the homozygous genotypes for VPS37C (rs7104333, A/A), MPG (rs1013358, C/C) genes or the heterozygous genotype for ARNT gene (rs1889740, rs2228099, rs2256355, rs2864873), GSTA4 (rs17614751) and APOBR/IL27 (rs17855750) were significantly associated with increased risk of bladder cancer development compared to reference group (OR 2.53, 2.34, 1.99, 2.00, 2.00, 1.47, 1.96 and 2.27 respectively). We have also found that non-smokers patients harboring heterozygous genotypes for ARNT/rs2864873 (A > G), ARNT/ rs1889740 (C > T) or GSTA4/rs17614751 (G-A) were respectively at 2.775, 3.069 and 6.608-fold increased risk of Bca development compared to non-smokers controls with wild genotypes. Moreover the ARNT CT (rs1889740), ARNT CG (rs2228099), ARNT TC (rs2864873) and GSS GA genotypes were associated with an increased risk of BCa even in absence of professional risk factors. Finally the decision-tree analysis produced a three major BCa classes. These three classes were essentially characterized by an intensity of tobacco use more than 20 pack years (PY) and the CYP1A2 (rs762551) genotype. CONCLUSIONS: The determined association between environmental factors, genetic variations and the risk of Bca development may provide additional information to urologists that may help them for clinical assessment and treatment decisions. Nevertheless, the underlying mechanisms through which these genes or SNPs affect the clinical behavior of BCas require further studies.

Association of a common genetic variant (insertion/deletion) in ACE gene with prostate cancer susceptibility in a Tunisian population.

BACKGROUND: Angiotensin-converting enzyme (ACE) plays a pivotal role in several pathologies including cancers. The association of insertion/deletion (I/D) polymorphism of the ACE gene with prostate cancer (PC) risk remains controversial. We aimed to investigate for the first time, to our Knowledge, in North Africa the potential relationship between ACE I/D polymorphism with PC susceptibility and clinical outcomes of PC patients. METHODS: This case-control study included 143 healthy individuals and 124 patients diagnosed with PC. Using genomic DNA, the samples were genotyped for ACE I/D polymorphism by polymerase chain reaction (PCR). RESULTS: We found that The D allele is significantly associated with an increased risk of PC and D/D + D/I genotypes were at 3 times increased risk of PC ([p = 0.005], OR = 2.95, IC 95% = 1.26-7.09) compared with I/I genotype (p = 0.003, OR = 0.3, IC 95% = 0.12-0.74). We observed an association between D/D and D/I genotypes with advanced age (≥70 years) (p = 0.014; r2  = 0.22). Furthermore, there is a significant prediction of advanced Gleason score ≥8 based on epidemiological parameters and ACE genotype (p = 0.000; R2  = 0.349), although no significant association was observed with stage and metastasis. CONCLUSION: The ACE I/D polymorphism is likely to predispose to PC and could play a role in PC progression and aggressiveness.

Polymorphisms in NQO1 and MPO genes and risk for bladder cancer in Tunisian population.

BACKGROUND: NAD (P) H: quinone oxidoreductase (1) (NQO1-HGNC: 2874) and myeloperoxidase (MPO-HGNC: 7218) are two enzymes involved in phase II of the xenobiotic metabolism pathway. METHODS: In this study, a case-control analysis was conducted to investigate the relationship between genetic variations in the NQO1 (C609T, rs1800566; IVS1-27 C >G, rs689452) and MPO (G463A, rs2333227) genes and the risk for bladder cancer among Tunisian population. RESULTS: We have found that the MPO 463GA genotype was associated with a decreased risk of developing bladder cancer (p = 0.049; OR = 0.696; 95% CI 0.484-0.999). In contrast, we have found that the NQO1 609CT genotype could increase the risk of bladder cancer patients (p = 0.0039; OR = 1.454; 95% CI = 1.017-2.078). Moreover, patients with "NQO1 609 CT/IVS1-27 CG" genotype show a 2.180-fold increasing risk for developing bladder cancer in comparison to the control group with wild genotype. This OR is estimated at 5.6-fold in smokers patients with "NQO1 609 CT/IVS1-27 CG" genotype. Lastly, study findings suggest that the NQO1 IVS-27 *CG genotype (rs689452) is associated with a risk of progression to muscle invasive bladder cancer. CONCLUSION: Our study suggests that environmental risk factors in association to NQO1 genotypes (NQO1 609 CT/IVS1-27 CG) play an important role in the development of bladder cancer in Tunisian population.

The diagnostic applicability of A-type Lamin in non-muscle invasive bladder cancer.

PURPOSE: Lamin A is a major component of the nuclear lamina maintaining nuclear integrity, regulation of gene expression, cell proliferation, and apoptosis. Its deregulation in cancer has been recently reported to be associated with its prognosis. However, its clinical significance in non-muscle invasive bladder cancer (NMIBC) remains to be defined. MATERIAL/METHODS: Immunohistochemical staining and RT-qPCR were performed to screen the expression patterns of Lamin A/C protein and Lamin A mRNA respectively in 58 high and low grade NMIBC specimens. RESULTS: Lamin A/C protein was expressed only in the nucleus and less exhibited in NMIBC tissues compared to non-tumoral ones. On the other side, Lamin A mRNA was up-regulated in NMIBC compared to controls. Nevertheless, both expression patterns (protein and mRNA) were not correlated to clinical prognosis factors and were not able to predict the overall survival of patients with high-grade NMIBC. CONCLUSIONS: The deregulation of A-type Lamin is not associated with the prognosis of NMIBC, but it could serve as a diagnostic biomarker distinguishing NMIBC patients from healthy subjects suggesting its involvement as an initiator event of tumorigenesis in our cohort.

Uncovering the expression patterns and the clinical significance of miR-182, miR-205, miR-27a and miR-369 in patients with urinary bladder cancer.

BACKGROUND: Given the high recurrence and progression rates and the absence of reliable markers for early detection and prognosis prediction of patients with urothelial bladder cancer (BCa), the exploration of new biomarkers with high specificity is imperative. Mainly, microRNAs (miRNAs), which are involved in the initiation and the progression of BCa. Herein, the expression patterns of miR-182, miR-205, miR-27a and miR-369 were evaluated in patients with urothelial BCa. METHODS AND RESULTS: The expression levels of the miRNAs were investigated in 90 FFPE tissue samples (23 LG NMIBC, 44 HG NMIBC, 23 MIBC) and 10 non tumoral bladder tissues using TaqMan based RT-qPCR. Data analysis was performed using 2-ΔΔCT method. Correlation to clinical characteristics of the patients was performed using descriptive statistics and the receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic value of all miRNAs. MiR-27a, miR-205 and miR-369 were down-regulated whereas miR-182 was up-regulated in patients compared to controls (p < 0.001). MiR-205 and miR-182 positively segregate between NMIBC and MIBC (p = 0.002 and p = 0.000 respectively) whereas the distribution of miR-27a's expression among these tumor groups was almost significant (p = 0.05) and that of miR-369's expression was irrelevant (p = 0.618). Interestingly, miR-182 was discriminative between LG NMIBC and HG NMIBC (p < 0.001) and Ta/T1 tumors (p = 0.000). Furthermore, high levels of miR-182 were potentially predictive of progression in NMIBC patients (p = 0.01). CONCLUSION: Collectively, a selection of miRNAs was found to be aberrantly expressed in BCa suggesting a potential diagnostic value in BCa. In addition, the clinical value of miR-182 and miR-205 as potential prognosis biomarkers was highlighted. Indeed, our data provide additional insights into cancer biology. Further functional or target studies are mandatory to strengthen these findings.

miR-143 expression profiles in urinary bladder cancer: correlation with clinical and epidemiological parameters.

Hsa-mir-143 and hsa-let-7c have been reported to be deregulated in multiple neoplasms. The main purpose of this study was to investigate the expression of these miRNAs in bladder cancer (BCa) and to analyze the association between their expression profiles and clinical and epidemiological parameters. Ninety BCa specimens were included. Expression patterns of miR-143 and let-7c were assessed by qRT-PCR using Taqman specific probes. Validated and predicted targets of these miRNA's were identified using CSmiRTar and DAVID tools, respectively. miR-143 was downregulated in tumors compared to controls (mean fold-change (FC) = 0.076). Its expression was significantly higher in MIBC compared to NMIBC (p = 0,001). Its value as a potential biomarker discriminating non invasive tumors from the invasive ones was confirmed by ROC curve (AUC = 0.768; p = 0.0001). Also, this down-regulation positively correlates with frequency of tobacco use (p = 0,04) and chronic alcohol consumption (p = 0,04). Let-7c was overexpressed in BCa samples (mean (FC = 9.92) compared to non tumoral ones but was not associated to clinical and epidemiological parameters. A comprehensive overview of miR-143 targets and pathways implicated in BCa initiation, diagnosis or prognosis using bioinformatical analysis, was conducted. While both deregulated miRNAs may contribute to urothelial tumorigenesis, the deregulation of miR-143 was significantly correlated to epidemiological and clinical parameters.

Evaluating prognostic utility of preoperative Neutrophil to Lymphocyte Ratio and hsa-let-7g/c up-regulation in patients with urinary bladder cancer.

BACKGROUND: Stratification and risk-evaluation of bladder cancer (BCa) patients are far-reached issues, especially for those with non muscle invasive disease. Thus, setting-up biomarkers, especially after resection of the primary tumor, is crucial. Specifically, Neutrophil to lymphocyte ratio NLR and let-7 deregulation which have been preliminarily but not consistently described to be associated to unfavorable prognosis. OBJECTIVE: To explore the clinical value of pre-treatment Neutrophil to Lymphocyte Ratio (NLR), let-7c and let-7g's deregulation. METHODS: Data were extracted from ninety BCa samples. Pre-treatment NLR was estimated as the absolute neutrophil count divided by the absolute lymphocyte count. Expression patterns of let-7c and let-7g were assessed by qRT-PCR. Correlation with clinical characteristics was performed by descriptive statistics. RESULTS: Both let-7 miRs were upregulated. Interestingly, let-7g was associated to pathological stage (p= 0.001) and tumor multiplicity (p= 0.003). NLR was associated to histological grade (p= 0.005) and clinical stage (p= 0.006). They were both associated to more aggressive phenotype and their worth as potential stratification biomarkers was confirmed by ROC curve. CONCLUSIONS: Our data demonstrated the potential clinical value of all markers, especially pretreatment NLR and let-7g. Further studies are recommended to confirm their utility in improving the clinical decision-making regarding treatment and follow-up scheduling.

The clinical and prognostic value of miR-9 gene expression in Tunisian patients with bladder cancer.

There is a major need for the identification of biomarkers, which are able to guide personalized therapy for bladder cancer, in particular after resection of the primary tumor. Specifically, miR-9 upregulation has been preliminarily associated with a more aggressive phenotype of bladder cancer, namely muscle-invasive bladder cancer (MIBC) or high-grade non-muscle-invasive bladder cancer (HG NMIBC). In order to explore the potential utility of miR-9 as a biomarker in bladder cancer, we have investigated its expression pattern in a sample of Tunisian patients who have undergone primary resection. This is a retrospective study performed on BCa samples from 90 patients (44 specimens of HG NMIBC, 23 specimens of LG NMIBC, and 23 specimens of MIBC). Ten samples from the non-tumoral zone of cystectomy specimens were used as controls. For each specimen, we measured miR-9 expression and correlated it with the clinical characteristics of the patients. Overall, miR-9 was overexpressed in MIBC compared to NMIBC specimens (median fold change [FC]: - 8.89 vs 1.41, p = 0.001). Similarly, miR-9 expression was significantly different in LG NMIBC, HG NMIBC and MIBC subgroups (median FC: 0.68, 2.14 and 8.89, respectively; p = 0.001). ROC analysis showed that miR-9 expression pattern could be used as potential biomarker for distinguishing NMIBC subgroups: indeed miR-9 expression is relatively low in LG NMIBC and high in HG NMIBC. The thresholds are estimated at 0.063 and 21.597, respectively. Moreover, miR-9 was associated with a higher risk of progression. This study suggests the clinical value of miR-9 as a prognostic factor in bladder cancer after tumor resection. Should the prognostic ability of miR-9 be confirmed in larger studies, also on different ethnic groups, it would be useful to investigate whether urine sampling-which is easier to perform, less invasive and less costly-can provide the same results as analysis on surgical specimens.

Polymorphisms in XPC gene and risk for prostate cancer.

Single nucleotide polymorphisms (SNP) in repair gene DNA such as XPC gene can reduce the DNA repair capacity (DRC). Reduced DRC induce genetic instability and may increase the susceptibility to prostate cancer (PC). We conducted a case-controls study to examine the relationship between XPC Lys939Gln and XPC-PAT polymorphisms and the risk for prostate cancer in Tunisian population. We have also correlated molecular results with clinical parameters (Gleason score and TNM status) and lifestyle factors (tobacco status, alcohol consumption, and exposition to professional risk factors) of prostate cancer patients. We have found that the XPC Lys939Gln polymorphism was not associated with a risk of prostate cancer. However the XPC PAT I/I genotype was found to be associated with 3.83-fold increased risk of prostate cancer compared to controls (p = 0.00006; OR 3.83; 95% CI (1.83-8.05)). The test of linkage disequilibrium showed that XPC-PAT polymorphism is in linkage disequilibrium with XPC Lys939Gln variants. The combined analysis of XPC Lys939Gln and XPC-PAT variants showed that patients who inherited (Lys/Gln + PAT D/D) genotypes were protected against prostate cancer development compared to controls. In the other hand, no significant association has been found between XPC polymorphisms and clinical parameters or between XPC polymorphisms and lifestyle factors.

Expression patterns and bioinformatic analysis of miR-1260a and miR-1274a in Prostate Cancer Tunisian patients.

Currently, microRNAs (miRs) represent great biomarkers in cancer due to their stability and their potential role in diagnosis, prognosis and therapy. This study aims to evaluate the expression levels of miRs-1260 and -1274a in prostate cancer (PC) samples and to identify their eventual targets by using bioinformatic analysis. In this project, we evaluated the expression status of miRs-1260 and -1274a in 86 PC patients and 19 controls by using real-time quantitative PCR and 2-ΔΔCt method. Moreover, we retrieved validated and predicted targets of miRs from several datasets by using the "multiMir" R/Bioconductor package. We have found that miRs-1260 and -1274a were over-expressed in PC patients compared to controls (p < 1 × 10-5). Moreover ROC curve for miRs-1260 and 1274a showed a good performance to distinguish between controls group and PC samples with an area under the ROC curve of 0.897 and 0.784 respectively. However, no significant association could be shown between these two miRs and clinical parameters such as PSA levels, Gleason score, tumor stage, D'Amico classification, lymph node metastasis statues, tumor recurrence, metastasis status and progression after a minimum of 5 years follow-up. Finally, a bioinformatic analysis revealed the association between these two miRs and several targets implicated in prostate cancer initiation pathways.

Distribution of xenobiotic metabolising enzyme genotypes in different Tunisian populations.

BACKGROUND: The N-acetyltransferase 2 (NAT2) and glutathione transferase enzymes play a crucial role in the metabolism of xenobiotics. Genetic polymorphisms affecting these enzymes can modify their activities with an effect on individual susceptibility for different pathologies. These metabolic phenotypes occur with varying prevalence in different populations. AIM: This study sought to analyse the prevalence of important allelic variants of NAT2, GSTM1 and GSTT1 in different Tunisian populations and compare them to other previously reported data. SUBJECTS AND METHODS: A total of 253 unrelated subjects from different Tunisian populations participated in this study. Subjects were examined with respect to the frequency of slow NAT2, GSTM1*0 and GSTT1*0 genotypes. RESULTS: The frequency of 'slow' NAT2, GSTM1*0 and GSTT1*0 genotypes in the Tunisian population were, respectively, estimated at 23.3%, 53.75% and 29.24%. The frequency of slow NAT2 and GSTM1*0 genotypes were significantly different between the North, Centre and South of Tunisia. However, this study doesn't report any significant differences in the genotype distribution between Cosmopolitan, Arab and Berber populations. CONCLUSIONS: In conclusion, these data indicate that the Tunisian population is highly heterogenic and, therefore, a strict definition of the populations involved in studies investigating the clinical effect of polymorphisms is required.

Association of genetic variation in IKZF1, ARID5B, CDKN2A, and CEBPE with the risk of acute lymphoblastic leukemia in Tunisian children and their contribution to racial differences in leukemia incidence.

Recent genome-wide association studies (GWAS) focusing on pediatric acute lymphoblastic leukemia (ALL), the most common malignancy in children younger than 15 years old, have found evidence that single-nucleotide polymorphisms (SNPs) in IKZF1 (7p12.2), ARID5B (10q21.2), CDKN2A (9p21.3), and CEBPE (14q11.2) are strongly associated to the risk of developing pediatric ALL. These studies have been conducted in European and Thai populations, and it is unclear whether these observations generalize to other populations with a lower incidence of pediatric ALL. In order to explore the impact of these variants on pediatric ALL risk in the Tunisian population, we genotyped 58 cases of pediatric ALL and 150 controls for SNPs rs4132601 (7p12.2), rs7089424 (10q21.2), rs3731217 (9p21.3), and rs2239633 (14q11.2). Our results, which are consistent with findings in European populations, show that 3 SNPs, i.e., rs4132601 (P = .00116, odds ratio [OR] = 2.78, 95% confidence interval [CI] = [1.42, 5.87]), rs7089424 (P = .0022, OR = 0.49, 95% CI = [0.31, 0.79]), and rs2239633 (P = .0010, OR = 0.47, 95% CI = [0.29, 0.75]) are significantly associated with a higher risk of developing pediatric ALL (P < .05). Furthermore, we show differences in allele frequencies in SNPs between Tunisian and Caucasian and/or Thai populations (e.g., CEBPE, rs2239633; population attributable risk [PAR] ∼15-fold the PAR of Thai population). These differences, combined with differences in linkage disequilibrium structure between populations and differences in size between populations, may contribute to racial differences in pediatric ALL incidence.

Polymorphisms in XPC, XPD and XPG DNA repair genes and leukemia risk in a Tunisian population.

Human DNA repair mechanisms protect the genome from DNA damage caused by endogenous and environmental agents. Polymorphisms in DNA repair genes and differences in repair capacity between individuals have been widely reported in different cancers. In this study we aimed to evaluate the associations between XPC Lys939Gln (rs2228001), XPD Lys751Gln (rs13181) and XPG Asp1104His (rs17655) polymorphisms and leukemia risk in a Tunisian population. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in 206 patients with leukemia and 206 healthy controls. We found increased risk of leukemia among subjects carrying the XPC 939Gln/Gln genotype (odds ratio [OR] = 2.48, 95% confidence interval [CI] = 1.353-4.560, p = 0.0042). Moreover, in subgroup analysis according to clinical types, patients with chronic myeloid leukemia (CML) showed a higher risk than patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (OR = 3.87, 95% CI = 1.820-8.237, p = 0.0003). However, the XPD 751Gln allele may be protective against CML and AML development, and no significant differences in genotype frequencies were observed for the XPG gene between patients and controls. Further studies with larger samples and risk factor information are needed.