Papers by Mariem Ben Rekaya
PLOS ONE
Background The aim of this study was to analyze PIK3CA mutations in exons 9 and 20 in breast canc... more Background The aim of this study was to analyze PIK3CA mutations in exons 9 and 20 in breast cancers (BCs) and their association with clinicopathological characteristics. Methods Mutational analysis of PIK3CA exon 9 and 20 was performed by Sanger sequencing in 54 primary BCs of Tunisian women. The associations of PIK3CA mutations with clinicopathological characteristics were analyzed. Results Fifteen exon 9 and exon 20 PIK3CA variants were identified in 33/54 cases (61%). PIK3CA mutations including pathogenic (class 5/Tier I) or likely pathogenic (class 4/Tier II) occurred in 24/54 cases (44%): 17/24 cases (71%) in exon 9, 5/24 cases (21%) in exon 20 and 2/24 cases (8%) in both exons. Of these 24 cases, 18 (75%) carried at least one of the three hot spot mutations: E545K (in 8 cases), H1047R (in 4 cases), E542K (in 3 cases), E545K/E542K (in one case), E545K/H1047R (in one case) and P539R/H1047R (in one case). Pathogenic PIK3CA mutations were associated with negative lymph node statu...
American Journal of Medical Genetics, 2001
A four‐month‐old white female, who was referred to us for genetic evaluation because of severe de... more A four‐month‐old white female, who was referred to us for genetic evaluation because of severe developmental delay, dysmorphic features, and bilateral cataracts, was found by routine cytogenetic analysis to have ring chromosome 16 in almost all cells analyzed. Ring chromosome 16 was confirmed and further delineated by fluorescence in situ hybridization (FISH). Breakpoints between loci D16S521 and KG8 on the short arm and D16S3121 and D16S303 on the long arm of chromosome 16 were determined by polymerase chain reaction (PCR) analysis. The deleted chromosome was of maternal origin. To our knowledge, this is the first case of ring chromosome 16 associated with bilateral cataracts. Comparison of previously reported cases with deletion of chromosome 16 and our case suggests the presence of cataract locus within 1 Mb of the terminus of 16q. © 2001 Wiley‐Liss, Inc.
DNA Repair, Feb 1, 2020
Nucleotide excision repair is a multistep process that recognizes and eliminates a spectrum of DN... more Nucleotide excision repair is a multistep process that recognizes and eliminates a spectrum of DNA damages. Five proteins, namely XPC, RAD23, Centrin 2, DDB1 and DDB2 act as a heterodimeric complex at the early steps of the NER pathway and play a crucial role in the removal of DNA lesions. Several exonic mutations on genes coding for these proteins have been identified as associated with Xeroderma-pigmentosum (XP), a rare monogenic disorder. However, the role of regulatory polymorphisms in disease development and inter-ethnic diversity is still not well documented. Due to the high incidence rate of XP in Tunisia, we performed a genotyping analysis of 140 SNPs found on these 5 genes in a set of 135-subjects representing the general Tunisian-population. An inter-ethnic comparison based on the genotype frequency of these SNPs have been also conducted. For the most relevant variants, we performed a comprehensive assessment of their functional effects. Linkage disequilibrium and principal component analysis showed that the Tunisian-population is an admixed and intermediate population between Sub-Saharan Africans and Europeans. Using variable factor maps, we identified a list of 20 polymorphisms that contribute considerably to the inter-ethnic diversity of the NER complex. In-silico functional analysis showed that SNPs on XPC, DDB1 and DDB2 are associated with eQTLs mainly DDB2-rs10838681 that seems to decrease significantly the expression level of ACP2 (p = 6.1 × 10 −26). Statistical analysis showed that the allelic frequency of DDB2-rs10838681 in Tunisia is significantly different from all other populations. Using rVarBase, we identified 5 variants on XPC, DDB1 and DDB2 that seem to alter the binding sites of several transcription factors considered as key players in DNA-repair pathways. Results presented in this study provide the first report on regulatory polymorphisms of the NER-complex genes in Tunisia. These results may also help to establish a baseline database for future association and functional studies.
Frontiers in Genetics, 2021
Xeroderma Pigmentosum (XP) is a rare genetic disorder affecting the nucleotide excision repair sy... more Xeroderma Pigmentosum (XP) is a rare genetic disorder affecting the nucleotide excision repair system (NER). It is characterized by an extreme sensitivity to sunlight that induces cutaneous disorders such as severe sunburn, freckling and cancers. In Tunisia, six complementation groups have been already identified. However, the genetic etiology remains unknown for several patients. In this study, we investigated clinical characteristics and genetic defects in two families with atypical phenotypes originating from the central region in Tunisia. Clinical investigation revealed mild cutaneous features in two patients who develop multiple skin cancers at later ages, with no neurological disorders. Targeted gene sequencing revealed that they carried novel variants. A homozygous variation in the ERCC4 gene c.1762G>T, p.V588F, detected in patient XP21. As for patient XP134, he carried two homozygous mutations in the DDB2 gene c.613T>C, p.C205R and c.618C>A, p.S206R. Structural mode...
Frontiers in Genetics, 2019
Xeroderma Pigmentosum-G Complementation Group helpful for early diagnosis. It also indicates that... more Xeroderma Pigmentosum-G Complementation Group helpful for early diagnosis. It also indicates that the genotype-phenotype correlation is not always coherent for patients with mild clinical features. These data therefore suggest that targeted NGS is a highly informative diagnostic strategy, which can be used for XP molecular etiology determination.
Annales de Dermatologie et de Vénéréologie, 2014
Annales de Dermatologie et de Vénéréologie, 2014
British Journal of Dermatology, 2009
Xeroderma pigmentosum (XP) is a rare genodermatosis predisposing to skin cancers. The disease is ... more Xeroderma pigmentosum (XP) is a rare genodermatosis predisposing to skin cancers. The disease is classified into eight groups. Among them, XP group A (XP-A) is characterized by the presence of neurological abnormalities in addition to cutaneous symptoms. In the present study, we report a particular family with XP-A in which some members showed an atypical clinical presentation, i.e. unexplained neurological abnormalities with discrete skin manifestations. Molecular investigation allowed identification of a novel XPA mutation and complete phenotype-genotype correlation for this new phenotypic expression of XP-A.
Molecular Genetics & Genomic Medicine
Frontiers in Genetics, 2020
Background: Deleterious mutations on BRCA1/2 genes are known to confer high risk of developing br... more Background: Deleterious mutations on BRCA1/2 genes are known to confer high risk of developing breast and ovarian cancers. The identification of these mutations not only helped in selecting high risk individuals that need appropriate prevention approaches but also led to the development of the PARP-inhibitors targeted therapy. This study aims to assess the prevalence of the most frequent BRCA1 mutation in Tunisia, c.211dupA, and provide evidence of its common origin as well as its clinicopathological characteristics. We also aimed to identify additional actionable variants using classical and next generation sequencing technologies (NGS) which would allow to implement cost-effective genetic testing in limited resource countries. Patients and Methods: Using sanger sequencing, 112 breast cancer families were screened for c.211dupA. A set of patients that do not carry this mutation were investigated using NGS. Haplotype analysis was performed to assess the founder effect and to estimate the age of this mutation. Correlations between genetic and clinical data were also performed. Results: The c.211dupA mutation was identified in 8 carriers and a novel private BRCA1 mutation, c.2418dupA, was identified in one carrier. Both mutations are likely specific to NorthEastern Tunisia. Haplotype analysis supported the founder effect of c.211dupA and showed its recent origin. Phenotype-genotype correlation showed that both BRCA1 mutations seem to be associated with a severe phenotype. Whole Exome Sequencing (WES) analysis of a BRCA negative family revealed a Variant of Unknown Significance, c.3647C > G on RAD50. Molecular modeling showed that this variant could be classified as deleterious as it is responsible for destabilizing the RAD50 protein structure. Variant prioritization and pathway analysis of the WES data showed additional interesting candidate genes including MITF and ANKS6.
Additional file 1: Table S1. Gene set enrichment analysis. Table S2. Summary of SNPs and Indels i... more Additional file 1: Table S1. Gene set enrichment analysis. Table S2. Summary of SNPs and Indels identified in the 7 BRCAx sequenced Tunisian breast cancer families. Table S3. Putative predisposition family-specific genes in several WES studies using the family-based approach.
Additional file 2: Figure S1. Biological networks and Enriched gene ontology pathways identified ... more Additional file 2: Figure S1. Biological networks and Enriched gene ontology pathways identified by the functional annotation analysis. Enrichment network of the shared candidate disease genes and their upstream regulator based on biological processes using ClueGO Cytoscape plugin. Hyper-geometric (right-handed) enrichment distribution tests, with a p-value significance level of â ¤ 0.05, followed by the Bonferroni adjustment for the terms and leading term groups were selected based on the highest significance. The node size and deeper color indicates greater significance of the enrichment.
Figure S1 GTEX Boxplots representing the most significant eQTL results for variant rs9911630 in b... more Figure S1 GTEX Boxplots representing the most significant eQTL results for variant rs9911630 in breast mammary tissue. Box plots represent the expression levels of the indicated transcripts with respect to the rs9911630 genotypes. Expression levels are shown for (a) NBR2 gene, (b) CTD-3199â J23.6 gene and (c) LINC00910 gene. Horizontal bars indicate mean expression level per genotype. Additional information on the eQTL p values are reported in Table 1. Figure S2 Alignment of the sequence around rs9911630 with binding site of (a) bmo-miR-3287, (b) ssa-miR-19d-5p and (c) mse-miR-2766. The SNP is shown in red and the allele binding the microRNA is also shown. Figure S3 Contributions of variables (SNPs and populations) in Dim1 and Dim2. The contribution of each tested variable (based on their variants frequencies) in the general variability between the different selected populations shown on the PCA (a) to the first dimension of the PCA (Dim1 for the variability between African and non-...
Table S1 Breast cancer loci and variants investigated in the Tunisian population. Table S2 Data s... more Table S1 Breast cancer loci and variants investigated in the Tunisian population. Table S2 Data sources for in silico analyses of variants with high RegulomeDB scores. Table S3 Allelic frequency of the selected breast cancer polymorphisms and comparison of these frequencies between Tunisian and HapMap populations (Pairwise pvaluesâ
1 Université Tunis El Manar, Institut Pasteur de Tunis, Laboratoire de Génomique Biomédicale et O... more 1 Université Tunis El Manar, Institut Pasteur de Tunis, Laboratoire de Génomique Biomédicale et Oncogénétique, Tunis, Tunisie 2 Dermatology Department, Charles Nicolle Hospital, Tunis, Tunisie 3 Department of Medical Oncology, Hôpital Abderrahman Mami, Ariana, Tunisie 4 Experimental and Human Anatomo-Pathology Department, Institut Pasteur de Tunis, Université El Manar de Tunis, Tunis, Tunisie 5 Laboratoire d’Histologie et Cytogénétique Institut Pasteur de Tunis, Université El Manar de Tunis, Tunis, Tunisie
Frontiers in Oncology, 2021
BackgroundBreast cancer is the world’s most common cancer among women. It is becoming an increasi... more BackgroundBreast cancer is the world’s most common cancer among women. It is becoming an increasingly urgent problem in low- and middle-income countries (LMICs) where a large fraction of women is diagnosed with advanced-stage disease and have no access to treatment or basic palliative care. About 5-10% of all breast cancers can be attributed to hereditary genetic components and up to 25% of familial cases are due to mutations in BRCA1/2 genes. Since their discovery in 1994 and 1995, as few as 18 mutations have been identified in BRCA genes in the Tunisian population. The aim of this study is to identify additional BRCA mutations, to estimate their contribution to the hereditary breast and ovarian cancers in Tunisia and to investigate the clinicopathological signatures associated with BRCA mutations.MethodsA total of 354 patients diagnosed with breast and ovarian cancers, including 5 male breast cancer cases, have been investigated for BRCA1/2 mutations using traditional and/or next ...
DNA Repair, 2020
Nucleotide excision repair is a multistep process that recognizes and eliminates a spectrum of DN... more Nucleotide excision repair is a multistep process that recognizes and eliminates a spectrum of DNA damages. Five proteins, namely XPC, RAD23, Centrin 2, DDB1 and DDB2 act as a heterodimeric complex at the early steps of the NER pathway and play a crucial role in the removal of DNA lesions. Several exonic mutations on genes coding for these proteins have been identified as associated with Xeroderma-pigmentosum (XP), a rare monogenic disorder. However, the role of regulatory polymorphisms in disease development and inter-ethnic diversity is still not well documented. Due to the high incidence rate of XP in Tunisia, we performed a genotyping analysis of 140 SNPs found on these 5 genes in a set of 135-subjects representing the general Tunisian-population. An inter-ethnic comparison based on the genotype frequency of these SNPs have been also conducted. For the most relevant variants, we performed a comprehensive assessment of their functional effects. Linkage disequilibrium and principal component analysis showed that the Tunisian-population is an admixed and intermediate population between Sub-Saharan Africans and Europeans. Using variable factor maps, we identified a list of 20 polymorphisms that contribute considerably to the inter-ethnic diversity of the NER complex. In-silico functional analysis showed that SNPs on XPC, DDB1 and DDB2 are associated with eQTLs mainly DDB2-rs10838681 that seems to decrease significantly the expression level of ACP2 (p = 6.1 × 10 −26). Statistical analysis showed that the allelic frequency of DDB2-rs10838681 in Tunisia is significantly different from all other populations. Using rVarBase, we identified 5 variants on XPC, DDB1 and DDB2 that seem to alter the binding sites of several transcription factors considered as key players in DNA-repair pathways. Results presented in this study provide the first report on regulatory polymorphisms of the NER-complex genes in Tunisia. These results may also help to establish a baseline database for future association and functional studies.
Journal of Translational Medicine, 2018
Background: A family history of breast cancer has long been thought to indicate the presence of i... more Background: A family history of breast cancer has long been thought to indicate the presence of inherited genetic events that predispose to this disease. In North Africa, many specific epidemio-genetic characteristics have been observed in breast cancer families when compared to Western populations. Despite these specificities, the majority of breast cancer genetics studies performed in North Africa remain restricted to the investigation of the BRCA1 and BRCA2 genes. Thus, comprehensive data at a whole exome or whole genome level from local patients are lacking. Methods: A whole exome sequencing (WES) of seven breast cancer Tunisian families have been performed using a family-based approach. We focused our analysis on BC-TN-F001 family that included two affected members that have been sequenced using WES. Relevant variants identified in BC-TN-F001 have been confirmed using Sanger sequencing. Then, we conducted an integrative analysis by combining our results with those from other WES studies in order to figure out the genetic transmission model of the newly identified genes. Biological network construction and protein-protein interactions analyses have been performed to decipher the molecular mechanisms likely accounting for the role of these genes in breast cancer risk. Results: Sequencing, filtering strategies, and validation analysis have been achieved. For BC-TN-F001, no deleterious mutations have been identified on known breast cancer genes. However, 373 heterozygous, exonic and rare variants have been identified on other candidate genes. After applying several filters, 12 relevant high-risk variants have been selected. Our results showed that these variants seem to be inherited in a family specific model. This hypothesis has been confirmed following a thorough analysis of the reported WES studies. Enriched biological process and proteinprotein interaction networks resulted in the identification of four novel breast cancer candidate genes namely MMS19, DNAH3, POLK and KATB6. Conclusions: In this first WES application on Tunisian breast cancer patients, we highlighted the impact of next generation sequencing technologies in the identification of novel breast cancer candidate genes which may bring new insights into the biological mechanisms of breast carcinogenesis. Our findings showed that the breast cancer predisposition in non-BRCA families may be ethnic and/or family specific.
BMC Cancer, 2018
Background: Breast cancer is the most common cancer in women worldwide. Around 50% of breast canc... more Background: Breast cancer is the most common cancer in women worldwide. Around 50% of breast cancer familial risk has been so far explained by known susceptibility alleles with variable levels of risk and prevalence. The vast majority of these breast cancer associated variations reported to date are from populations of European ancestry. In spite of its heterogeneity and genetic wealth, North-African populations have not been studied by the HapMap and the 1000Genomes projects. Thus, very little is known about the genetic architecture of these populations. Methods: This study aimed to investigate a subset of common breast cancer loci in the general Tunisian population and to compare their genetic composition to those of other ethnic groups. We undertook a genomewide haplotype study by genotyping 135 Tunisian subjects using the Affymetrix 6.0-Array. We compared Tunisian allele frequencies and linkage disequilibrium patterns to those of HapMap populations and we performed a comprehensive assessment of the functional effects of several selected variants. Results: Haplotype analyses showed that at risk haplotypes on 2p24, 4q21, 6q25, 9q31, 10q26, 11p15, 11q13 and 14q32 loci are considerably frequent in the Tunisian population (> 20%). Allele frequency comparison showed that the frequency of rs13329835 is significantly different between Tunisian and all other HapMap populations. LDblocks and Principle Component Analysis revealed that the genetic characteristics of breast cancer variants in the Tunisian, and so probably the North-African populations, are more similar to those of Europeans than Africans. Using eQTl analysis, we characterized rs9911630 as the most strongly expression-associated SNP that seems to affect the expression levels of BRCA1 and two long non coding RNAs (NBR2 and LINC008854). Additional in-silico analysis also suggested a potential functional significance of this variant. Conclusions: We illustrated the utility of combining haplotype analysis in diverse ethnic groups with functional analysis to explore breast cancer genetic architecture in Tunisia. Results presented in this study provide the first report on a large number of common breast cancer genetic polymorphisms in the Tunisian population which may establish a baseline database to guide future association studies in North Africa.
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Papers by Mariem Ben Rekaya