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.

Identification a novel pathogenic LRTOMT mutation in Mauritanian families with nonsyndromic deafness.

PURPOSE: Although recessive mutations in GJB2 are the common genetic etiology of sensorineural hearing impairment (SNHI), variants in LRTOMT gene were also identified, mostly in Middle East and North African populations. METHODS: Using Sanger sequencing we screened the exon 7 of LRTOMT in a cohort of 128 unrelated Mauritanian children with congenital deafness. RESULTS: Only one biallelic missense mutation, predicted as pathogenic (c.179 T > C;p.Leu60Pro) was found at homozygous state in four families. This variant, not reported before, showed a deleterious effect by SIFT (score: 0.01) and a disease-causing effect by Mutation Taster (prob: 1). Exploration of the encoded protein 3D structure revealed a disruption from an organized α helix (in the normal protein structure) into a random conformation. Early fitting of a cochlear implant seemed to improve the audition ability of the mutation carrier. CONCLUSION: Further screening using a panel of deafness genes may expose other variants underlying hearing impairment in our population.

Screening of BRCA1/2 variants in Mauritanian breast cancer patients.

BACKGROUND AND STUDY AIM: Carrying a pathogenic BRCA1/2 variant increases greatly young women's risk of developing breast cancer (BC). This study aimed to provide the first genetic data on BC in Mauritania. METHODS: Using NGS based screening; we searched for BRCA1/2 variants in DNA samples from 137 patients diagnosed for hereditary BC. RESULTS: We identified 16 pathogenic or likely pathogenic (PV) variants carried by 38 patients. Two predominant BRCA1 PV variants were found: c.815_824dup and c.4986 + 6 T > C in 13 and 7 patients, respectively. Interestingly, three novels BRCA1/2 predicted pathogenic variants have also been detected. Notably, no specific distribution of BRCA1/2 variants was observed regarding triple negative breast cancer (TNBC) or patient gender status. CONCLUSIONS: In this first genetic profiling of BC in Mauritania, we identified a substantial number of BRCA1/2 pathogenic variants. This finding could be important in the future diagnosis and prevention policy of hereditary BC in Mauritania.

Splice-altering variant of PJVK gene in a Mauritanian family with non-syndromic hearing impairment.

PJVK gene was recently shown to create hypervulnerability to sound in humans and was the first human gene implicated in non-syndromic hearing impairment due to neural defect. Targeted next-generation sequencing of over 150 known deafness genes was performed in the proband. Sanger sequencing was used to validate the PJVK variant and confirm familial segregation of the disease. A minigene-based assay has been performed to assess the impact of the variant on splicing. We identified a novel c.550-6A > G acceptor splice-site variant in the PJVK gene in the homozygous state in a Mauritanian child with severe to profound congenital deafness. The substitution was located in intron 4. The effect of the variation was demonstrated by a minigene assay which showed that the variation, an insertion of an additional 5 bp, created a new splice site resulting in the appearance of a premature stop codon (p.Phe184Tyrfs*26) and likely a truncated protein. This result constitutes a new splice-site variant report in the PJVK gene leading to DFNB59 type associated with autosomal recessive non-syndromic hearing impairment (ARNSHI).

Prognostic value of Epstein-Barr virus DNA load in nasopharyngeal carcinoma: a meta-analysis.

The present meta-analysis was conducted to evaluate the prognostic value of pre and post-Epstein Barr Virus (EBV) DNA load testing and to assess the clinical benefit of using this molecular approach in the prognosis for a better nasopharyngeal carcinoma (NPC) management. Relevant studies were searched in different database until May 2020. Patient´s outcomes overall survival (OS), disease free survival (DFS), progression-free survival (PFS), distant-metastasis-free survival (DMFS), and local-regional-failure-free survival (LRFS), hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted from selected studies. The association of pre and post-EBV DNA load and survival outcomes was assessed using review manager and the pooled HRs with 95% CIs were calculated. Twenty-six eligible studies were included in this meta-analysis, with a total of 9966 patients. Pooled HRs showed that EBV DNA levels before and after treatment are significantly associated with survival outcomes, with HR (95% CI) of 2.09 [1.74, 2.51] for OS, 1.77 [1.19, 2.62] for DFS, 2.53 [2.18, 2.92] for DMFS, 1.78 [1.45, 2.19] for LRFS and 2.17 [1.91, 2.47] for PFS in pre-EBV DNA, and an HR (95%) of 4.52 [2.44, 8.36], 4.08 [2.38, 6.99], 5.59 [ 3.58, 8.71] and 8.88 [5.29, 14.90] for OS, DFS and PFS and DMFS in post-EBV DNA, respectively. High pre and post-EBV DNA levels were significantly associated with poor NPC patient´s survival outcomes; which clearly confirm the high interest to introduce viral EBV DNA load as a prognostic biomarker for NPC management.