Genetic variations in CYP2A6, CYP2E1, GSTM1, GSTT1 genes and the risk of Nasopharyngeal carcinoma in North African population.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy associated with both genetic and environmental factors. Polymorphic deletions of the phase I and phase II genes involved in the detoxification of potential carcinogens may be a risk factor for nasopharyngeal carcinoma. In this study, we investigated the relationship between CYP2E1 (rs3813867), CYP2A6, GSTM1(rs1183423000) and GSTT1(rs1601993659) gene variations and NPC risk in North African countries with the highest incidence of NPC (Morocco, Algeria and Tunisia). and the evaluation of the potential use of these variants as potential biomarkers for NPC management. METHODS: A total of 600 NPC cases and 545 controls frequency-matched on ethnicity, sex, age and childhood household type, were recruited from three North African countries (Morocco, Algeria and Tunisia) and analysed. Genotyping of CYP2A6 and CYP2E1(rs3813867) was performed by polymerase chain reaction restriction (PCR)-fragment length polymorphism (RFLP) analysis and the GSTM1 (rs1183423000) and GSTT1(rs1601993659) genetic variations were evaluated using the PCR technique. RESULTS: The genotype distributions of CYP2E1(rs3813867), CYP2A6, GSTM1(rs1183423000) and GSTT1(rs1601993659) genotypes did not differ significantly among NPC cases and controls (p > 0.05). Furthermore, our data did not reveal any association with smoking and the studied variants, even when the samples were stratified by the duration period of smoking. CONCLUSION: In this large studied North African population, our findings suggest that the functional CYP2E1, CYP2A6, GSTM1 and GSTT1 variations did not influence NPC susceptibility.

Molecular evaluation of human papillomavirus as an oncogenic biomarker in prostate cancer.

BACKGROUND: Prostate cancer (PCa) is one of the most common tumors in men, regardless of ethnicity and demographics. In many risk factors causing PCa, genes and viral infections are strong candidates for the development of prostate tumors. Indeed, tissue infections of PCa have been reported by the presence of several types of viruses including Human Papillomaviruses (HPV). OBJECTIVE: the present study was planned to determine whether HPV DNA could be detected in the blood of known men with prostate cancer and to assess the potential association between HPV infection and clinico-pathological characteristics of the patients. MATERIALS AND METHODS: In order to achieve our objectives, 150 liquid blood samples were taken from Moroccan patients, 100 patients with PCa, and 50 control cases. The viral DNA was extracted, calibrated and the target genes were amplified by PCR using specific primers and the use of 2% agarose gel with visualization under UV. RESULTS: Of the 100 samples tested, (10%) were infected with HPV), However, none of the control cases were infected with HPV. The analysis of the data made it possible to establish a correlation between the frequency of the viral infection of the human papilloma and the tumoral criteria. CONCLUSION: Therefore, this study strengthens the potential role of HPV as a cofactor in prostate cancer development, and we propose that infection with this virus may be involved in the development of PCa metastases.

Association between single nucleotide polymorphisms in DNA repair genes and the efficacy of radiotherapy in nasopharyngeal carcinoma patients.

Introduction: Single nucleotide polymorphisms (SNPs) in DNA repair genes are mainly correlated with the response to radiotherapy in nasopharyngeal cancer (NPC). In NPC patients, previous research has studied the association between X-ray repair cross-complementing group 1 and 3 (XRCC1 and XRCC3) polymorphisms and radio-therapeutic response. The objective of our study was to test the association between XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms and the response to radiotherapy in the NPC Moroccan population. Material and methods: A total of 100 patients with NPC were genotyped for polymorphisms in XRCC1 and XRCC3 genes. Results: The results revealed that the genotypes and alleles of both SNPs did not show any significant association with clinical stages (for XRCC1 Arg399Gln: p [genotype] = 0.559; p [allele] = 0.440) and (for XRCC3 Thr241Met: p [genotype] = 0.638; p [allele] = 0.567). Moreover, in the study of the association between the polymorphisms and radiotherapy, the response to radiation therapy between genotypes and alleles was not statistically significant (for XRCC1 Arg399Gln p [genotype] = 0.583; p [allele] = 0.459) and (for XRCC3 Thr241Met p [genotype] = 0.660; p [allele] = 0.590). Conclusions: The present study suggests that XRCC1 Arg399Gln polymorphism does not have any impact on the radio-therapeutic response in Moroccan NPC patients whereas XRCC3 Thr241Met polymorphism may act as a prognostic indicator for NPC patients treated with radiotherapy. However, studies with a larger sample are needed to confirm our results.

Circulating cell-free epstein-barr virus DNA levels and clinical features in Moroccan patients with nasopharyngeal carcinoma.

BACKGROUND: The identification of effective prognosis biomarkers for nasopharyngeal carcinoma (NPC) is crucial to improve treatment and patient outcomes. In the present study, we have attempted to evaluate the correlation between pre-treatment plasmatic Epstein-Barr virus (EBV) DNA load and the conventional prognostic factors in Moroccan patients with NPC. METHODS: The present study was conducted on 121 histologically confirmed NPC patients, recruited from January 2017 to December 2018. Circulating levels of EBV DNA were measured before therapy initiation using real-time quantitative PCR. RESULTS: Overall, undifferentiated non-keratinizingcarcinoma type was the most common histological type (90.1 %), and 61.8 % of patients were diagnosed at an advanced disease stage (IV). Results of pre-treatment plasma EBV load showed that 90.9 % of patients had detectable EBV DNA, with a median plasmatic viral load of 7710 IU/ml. The correlation between pre-treatment EBV DNA load and the conventional prognostic factors showed a significant association with patients' age (p = 0.01), tumor classification (p = 0.01), lymph node status (p = 0.003), metastasis status (p = 0.00) and overall cancer stage (p = 0.01). Unexpectedly, a significant higher level of pre-treatment EBV DNA was also found in plasma of NPC patients with a family history of cancer (p = 0.04). The risk of NPC mortality in patients with high pretreatment EBVDNA levels was significantly higher than that of those with low pre-treatment plasma EBV-DNA levels (p < 0.05). Furthermore, patients with high pre-treatment EBV-DNA levels (≥ 2000, ≥ 4000) had a significant low overall survival (OS) rates (p < 0.05). Interestingly, lymph node involvement, metastasis status and OS were found to be the most important factors influencing the EBV DNA load in NPC patients. CONCLUSIONS: The results of the present study clearly showed a high association between pre-treatment EBV DNA load, the crucial classical prognostic factors (T, N, M and disease stage) of NPC and OS, suggesting that pre-treatment EBV DNA can be a useful prognostic biomarker in clinical decision-making and improving NPC treatment in Morocco.

Molecular docking analysis of α2-containing GABAA receptors with benzimidazoles derivatives.

It is of interest to study the binding capacity of "3-[2-(2-Amino-1H-benzo[d]imidazol-1-yl)ethyl]-1,3-oxazolidin-2-one" (OXB2) with the active site of gamma-aminobutyric acid (GABA) located in the GABA type A receptor (GABAAR) in comparison with different GABAA subtypes. Optimal binding features were observed with the α2ß2γ2 isoform (-8 kcal/mol). This is similar (-7.3 and -7.2 kcal/mol, respectively) for subtypes (α3ß2γ2 and α1ß2γ2). This implies that OXB2 binds preferentially to subtypes associated with anxiety (α2- and/or α3-containing receptors) linked molecules than with the subtype associated with sedation (α1-containing receptors). It is further noted that molecular dynamics simulation data of the complex (OXB2-GABAAR) shows adequate structural stability in aqueous environment. Moreover, relevant ADMET data is found adequate for further consideration.

Frequency of genomic mutations mediating resistance of Mycobacterium tuberculosis isolates to rifampicin in Northern Morocco.

Drug resistant tuberculosis (DR-TB) is challenging particularly in developing countries. As such, a previous investigation gave the first insight into the mutational status of the Rifampicin Resistance Determining Region (RRDR) of rpoB gene among a restricted number of MTB patients' residents in the Northern Morocco. The purpose of this study was to investigate rpoB mutation types and frequencies associated with resistance to Rifampicin in a larger panel of MTB patients and to evaluate the usefulness of these mutations to improve the diagnosis of resistance to Rifampicin. A panel of 301 consecutive sputum samples belonging to patients suscpected of having TB from Northern Morocco was collected at the Pasteur Institute of Tangier between 2014-2017. Samples were subjected to conventionel microbiological tests. Evaluation of rpoB muational status was assessed by PCR amplification and sequencing of the RRDR of the rpoB gene. DST results showed that 26.4% of strains were MDR. Sequencing results reported single point mutations in 36 of 65 RIFR isolates of which two had two mutations. Aminoacid substitutions in the codon Ser531Leu occurred at the highest frequency (34.46%). Overall, 10 aminoacid substitutions have been registered, and the H526S substitution was reported for the first time. The present study highlighted that resistance to RIF is a reliable marker of MDR-TB, the common mutations successfully detected in the rpoB 531, rpoB526 and rpoB516 codons provide a foundation for the implementation of molecular approaches such as Hain and GeneXpert as a routine tests to detect DR-TB. However, considerable work is still necessary to identify extensive mutations associated with DR-TB.

BRCA1 c.68_69delAG (exon2), c.181T>G (exon5), c.798_799delTT and 943ins10 (exon11) mutations in Burkina Faso.

The worldwide variation of BRCA mutations is well known. The c.68_69delAG, c.181T>G, c.798_799delTT mutations in BRCA1 were observed in Moroccan, Algerian and Tunisian Breast Cancer families and were described founder mutation in Northern Africa. The 943ins10 is also recognized a founder mutation in West Africa. To our knowledge no study has been published on BRCA1/2 germline mutations and hereditary breast cancer (HBC) in population of Burkina Faso. The aim of the present study (first in Burkina Faso) was to screen for these four mutations in 15 unrelated patients with HBC. Mutation analysis was performed by Sanger sequencing of coding exon2, Exon5 and exon11A sequences of the BRCA1 gene. Blood specimens of 15 patients from Burkina Faso, with HBC were collected at the University Hospital Yalgado OUEDRAOGO (CHU-YO) of Ouagadougou in Burkina Faso. c.68_69delAG (exon2), c.181T>G (exon5), c.798_799delTT and 943ins10 (exon11) mutations were not detected in any of the 15 women diagnosed with family breast cancer history. Genetic analysis in this study, we show that targeting relevant exons in BRCA1 genes did not allow detection of mutations in the population of Burkina Faso. Therefore, such an approach may be of interest to perfom a complete sequencing of BRCA1 and BRCA2 genes in families at a high risk of developing breast cancer in Burkina Faso.

Naturally occurring capsid protein variants L1 of human papillomavirus genotype 16 in Morocco.

HPV L1 protein is a corner stone in HPV structure, it's involved in the formation of the viral capsid; widely used as a systematic material and considered as the main component in vaccines development and production. The present study aims to characterize genetic variation of L1 gene of HPV 16 specimens and to evaluate in silico the impact of major variants on the epitope change affecting its conformational structure. A fragment of L1 gene from 35 HPV 16 confirmed specimens were amplified by PCR and sequenced. Overall, five amino acids residues changes were reported: T390P in 16 specimens, M425I and M431I in 2 cases, insertion of Serine at 460 and aspartic acid deletion at position 477 in all analyzed cases. The 3D generated model showed that T389P amino acid substitution is located in the H-I loop; the two substitutions M424I and M430I are both located in the H2 helice. The Serine insertion and aspartic acid deletion are located in the H4 helice and B-C loop, respectively. Superimposition of sequences' structures showed that they share a very similar conformation highlighting that the reported amino acids variations don't affect the structure of the L1 protein. However T389P, located in the H-I loop identified as an immunogenetic region of L1 capsid, was reported in 51.4% of cases could interact with vaccines induced monoclonal antibodies suggesting a potential impact on the efficacy of available anti-HPV vaccines.

Recent Progress in Triple Negative Breast Cancer Research.

Triple-negative breast cancer (TNBC) is defined as a type of breast carcinoma that is negative for expression of oestrogene and progesterone hormone receptors (ER, PR) and HER2. This form of breast cancer is marked by its aggressiveness, low survival rate and lack of specific therapies. Recently, important molecular characteristics of TNBC have been highlighted and led to the identification of some biomarkers that could be used in diagnosis, as therapeutic targets or to assess the prognosis. In this review, we summarize recent progress in TNBC research focusing on the genetic and epigenetic alterations of TNBC and the potential use of these biomarkers in the targeted therapy for better management of TNBC.

Breast cancer in Morocco: a literature review.

In Morocco, breast cancer is the most prevalent cancer in women and a major public health problem. Several Moroccan studies have focused on studying this disease, but more are needed, especially at the genetic and molecular levels. It is therefore interesting to establish the genetic and molecular profile of Moroccan patients with breast cancer. In this paper, we will highlight some pertinent hypotheses that may enhance breast cancer care in Moroccan patients. This review will give a precise description of breast cancer in Morocco and propose some new markers for detection and prediction of breast cancer prognosis.

Direct sequencing for rapid detection of multidrug resistant Mycobacterium tuberculosis strains in Morocco.

BACKGROUND: Tuberculosis (TB) is a major public health problem with high mortality and morbidity rates, especially in low-income countries. Disturbingly, the emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB cases has worsened the situation, raising concerns of a future epidemic of virtually untreatable TB. Indeed, the rapid diagnosis of MDR TB is a critical issue for TB management. This study is an attempt to establish a rapid diagnosis of MDR TB by sequencing the target fragments of the rpoB gene which linked to resistance against rifampicin and the katG gene and inhA promoter region, which are associated with resistance to isoniazid. METHODS: For this purpose, 133 sputum samples of TB patients from Morocco were enrolled in this study. One hundred samples were collected from new cases, and the remaining 33 were from previously treated patients (drug relapse or failure, chronic cases) and did not respond to anti-TB drugs after a sufficient duration of treatment. All samples were subjected to rpoB, katG and pinhA mutation analysis by polymerase chain reaction and DNA sequencing. RESULTS: Molecular analysis showed that seven strains were isoniazid-monoresistant and 17 were rifampicin-monoresistant. MDR TB strains were identified in nine cases (6.8%). Among them, eight were traditionally diagnosed as critical cases, comprising four chronic and four drug-relapse cases. The last strain was isolated from a new case. The most recorded mutation in the rpoB gene was the substitution TCG > TTG at codon 531 (Ser531 Leu), accounting for 46.15%. Significantly, the only mutation found in the katG gene was at codon 315 (AGC to ACC) with a Ser315Thr amino acid change. Only one sample harbored mutation in the inhA promoter region and was a point mutation at the -15p position (C > T). CONCLUSION: The polymerase chain reaction sequencing approach is an accurate and rapid method for detection of drug-resistant TB in clinical specimens, and could be of great interest in the management of TB in critical cases to adjust the treatment regimen and limit the emergence of MDR and XDR strains.