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Mezzi N, Messaoud O, Mkaouar R, Zitouna N, Romdhane S, Abdessalem G, Charfeddine C, Maazoul F, Ouerteni I, Hamdi Y, Zaouak A, Mrad R, Abdelhak S, Romdhane L. Spectrum of Genetic Diseases in Tunisia: Current Situation and Main Milestones Achieved. Genes (Basel) 2021; 12:1820. [PMID: 34828426 PMCID: PMC8617973 DOI: 10.3390/genes12111820] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023] Open
Abstract
Genetic diseases in Tunisia are a real public health problem given their chronicity and the lack of knowledge concerning their prevalence and etiology, and the high rates of consanguinity. Hence, we performed systematic reviews of the literature in order to provide a more recent spectrum of these disorders and to expose the challenges that still exist to tackle these kinds of diseases. A manual textual data mining was conducted using MeSH and PubMed databases. Collected data were classified according to the CIM-10 classification and the transmission mode. The spectrum of these diseases is estimated to be 589 entities. This suggests remarkable progress through the development of biomedical health research activities and building capacities. Sixty percent of the reported disorders are autosomal recessive, which could be explained by the high prevalence of endogamous mating. Congenital malformations (29.54%) are the major disease group, followed by metabolic diseases (22%). Sixty percent of the genetic diseases have a known molecular etiology. We also reported additional cases of comorbidity that seem to be a common phenomenon in our population. We also noticed that epidemiological data are scarce. Newborn and carrier screening was only limited to pilot projects for a few genetic diseases. Collected data are being integrated into a database under construction that will be a valuable decision-making tool. This study provides the current situation of genetic diseases in Tunisia and highlights their particularities. Early detection of the disease is important to initiate critical intervention and to reduce morbidity and mortality.
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Affiliation(s)
- Nessrine Mezzi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia
- Department of Biology, Faculty of Sciences of Bizerte, Université Tunis Carthage, Jarzouna 7021, Tunisia
| | - Olfa Messaoud
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia
| | - Rahma Mkaouar
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia
| | - Nadia Zitouna
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia
| | - Safa Romdhane
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia
| | - Ghaith Abdessalem
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia
| | - Cherine Charfeddine
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia
- High Institute of Biotechnology of Sidi Thabet, Biotechpole of Sidi Thabet, University of Manouba, Ariana 2080, Tunisia
| | - Faouzi Maazoul
- Department of Congenital and Hereditary Diseases, Charles Nicolle Hospital, Tunis 1002, Tunisia
| | - Ines Ouerteni
- Department of Congenital and Hereditary Diseases, Charles Nicolle Hospital, Tunis 1002, Tunisia
| | - Yosr Hamdi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia
- Laboratory of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia
| | - Anissa Zaouak
- Department of Dermatology, Research Unit Genodermatosis and Cancer LR12SP03, Habib Thameur Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1002, Tunisia
| | - Ridha Mrad
- Department of Congenital and Hereditary Diseases, Charles Nicolle Hospital, Tunis 1002, Tunisia
| | - Sonia Abdelhak
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia
| | - Lilia Romdhane
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia
- Department of Biology, Faculty of Sciences of Bizerte, Université Tunis Carthage, Jarzouna 7021, Tunisia
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Kay JE, Corrigan JJ, Armijo AL, Nazari IS, Kohale IN, Torous DK, Avlasevich SL, Croy RG, Wadduwage DN, Carrasco SE, Dertinger SD, White FM, Essigmann JM, Samson LD, Engelward BP. Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice. Cell Rep 2021; 34:108864. [PMID: 33730582 PMCID: PMC8527524 DOI: 10.1016/j.celrep.2021.108864] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/05/2021] [Accepted: 02/23/2021] [Indexed: 02/07/2023] Open
Abstract
N-Nitrosodimethylamine (NDMA) is a DNA-methylating agent that has been discovered to contaminate water, food, and drugs. The alkyladenine DNA glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we study Aag-knockout (Aag-/-) and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine [3MeA]) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switches from cancer to lethality simply by changing AAG levels. To understand the underlying basis for this observation, we integrate a suite of molecular, cellular, and physiological analyses. We find that unrepaired 3MeA is somewhat toxic, but highly mutagenic (promoting cancer), whereas excess strand breaks are poorly mutagenic and highly toxic (suppressing cancer and promoting lethality). We demonstrate that the levels of a single DNA repair protein tip the balance between blocks and breaks and thus dictate the disease consequences of DNA damage.
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Affiliation(s)
- Jennifer E Kay
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA
| | - Joshua J Corrigan
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA
| | - Amanda L Armijo
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 01239, USA
| | - Ilana S Nazari
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA
| | - Ishwar N Kohale
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 01239, USA
| | | | | | - Robert G Croy
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA
| | - Dushan N Wadduwage
- The John Harvard Distinguished Science Fellows Program, Harvard University, Cambridge, MA 02138, USA; Center for Advanced Imaging, Harvard University, Cambridge, MA 02138, USA
| | - Sebastian E Carrasco
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 01239, USA
| | | | - Forest M White
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 01239, USA
| | - John M Essigmann
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 01239, USA
| | - Leona D Samson
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 01239, USA
| | - Bevin P Engelward
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA.
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3
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Rotimi SO, Rotimi OA, Salhia B. A Review of Cancer Genetics and Genomics Studies in Africa. Front Oncol 2021; 10:606400. [PMID: 33659210 PMCID: PMC7917259 DOI: 10.3389/fonc.2020.606400] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/14/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer is the second leading cause of death globally and is projected to overtake infectious disease as the leading cause of mortality in Africa within the next two decades. Cancer is a group of genomic diseases that presents with intra- and inter-population unique phenotypes, with Black populations having the burden of morbidity and mortality for most types. At large, the prevention and treatment of cancers have been propelled by the understanding of the genetic make-up of the disease of mostly non-African populations. By the same token, there is a wide knowledge gap in understanding the underlying genetic causes of, and genomic alterations associated with, cancer among black Africans. Accordingly, we performed a review of the literature to survey existing studies on cancer genetics/genomics and curated findings pertaining to publications across multiple cancer types conducted on African populations. We used PubMed MeSH terms to retrieve the relevant publications from 1990 to December 2019. The metadata of these publications were extracted using R text mining packages: RISmed and Pubmed.mineR. The data showed that only 0.329% of cancer publications globally were on Africa, and only 0.016% were on cancer genetics/genomics from Africa. Although the most prevalent cancers in Africa are cancers of the breast, cervix, uterus, and prostate, publications representing breast, colorectal, liver, and blood cancers were the most frequent in our review. The most frequently reported cancer genes were BRCA1, BRCA2, and TP53. Next, the genes reported in the reviewed publications’ abstracts were extracted and annotated into three gene ontology classes. Genes in the cellular component class were mostly associated with cell part and organelle part, while those in biological process and molecular function classes were mainly associated with cell process, biological regulation, and binding, and catalytic activity, respectively. Overall, this review highlights the paucity of research on cancer genomics on African populations, identified gaps, and discussed the need for concerted efforts to encourage more research on cancer genomics in Africa.
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Affiliation(s)
- Solomon O Rotimi
- Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Biochemistry, Covenant University, Ota, Nigeria
| | - Oluwakemi A Rotimi
- Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Biochemistry, Covenant University, Ota, Nigeria
| | - Bodour Salhia
- Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Norris Comprehensive Cancer Centre, University of Southern California, Los Angeles, CA, United States
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Vermaut C, Leclerc J, Vasseur F, Wacrenier A, Lovecchio T, Boidin D, Rebergue MH, Cattan S, Manouvrier S, Lejeune S, Buisine MP. MSH2 c.1022T>C, p.Leu341Pro is a founder pathogenic variation and a major cause of Lynch syndrome in the North of France. Genes Chromosomes Cancer 2019; 59:111-118. [PMID: 31433521 DOI: 10.1002/gcc.22804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 08/16/2019] [Accepted: 08/16/2019] [Indexed: 11/10/2022] Open
Abstract
Interpretation of missense variants remains a major challenge for genetic diagnosis, even in well-known genes such as the DNA-mismatch repair (MMR) genes involved in Lynch syndrome. We report the characterization of a variant in MSH2: c.1022T>C, which was identified in 20 apparently unrelated families living in the North of France. A total of 150 patients from 20 families were included in this study. Family segregation studies, tumor analyses and functional analyses at both the RNA and protein levels were performed. Founder effect was evaluated by haplotype analysis.We show that MSH2 c.1022T>C is a missense variant (p.Leu341Pro) that affects protein stability. This variant is frequent in the North of France (7.7% of pathogenic variations identified in MMR genes), and is located on an ancestral haplotype. It is associated with a high risk of a broad tumor spectrum including brain and cutaneous cancers. The MSH2 c.1022T>C variant is a pathogenic founder variation associated with a high risk of cancer. These findings have important implications for genetic counseling and management of variant carriers.
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Affiliation(s)
- Catherine Vermaut
- Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Julie Leclerc
- Department of Biochemistry and Molecular Biology, Inserm UMR-S1172 - Jean-Pierre Aubert Research Center, Lille University, and Lille University Hospital, Lille, France
| | - Francis Vasseur
- Department of Biostatistics, Lille University and Lille University Hospital, Lille, France
| | - Agnes Wacrenier
- Department of Pathology, Lille University Hospital, Lille, France
| | - Tonio Lovecchio
- Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Denis Boidin
- Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | | | - Stephane Cattan
- Department of Gastroenterology, Lille University Hospital, Lille, France
| | - Sylvie Manouvrier
- Department of Clinical Genetics, Lille University Hospital, Lille, France.,Department of Clinical Genetics, Lille University EA 7364 - RADEME (Maladies RAres du Développement et du Métabolisme), and Lille University Hospital, Lille, France
| | - Sophie Lejeune
- Department of Clinical Genetics, Lille University Hospital, Lille, France
| | - Marie-Pierre Buisine
- Department of Biochemistry and Molecular Biology, Inserm UMR-S1172 - Jean-Pierre Aubert Research Center, Lille University, and Lille University Hospital, Lille, France
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Elloumi-Zghal H, Chaabouni Bouhamed H. Genetics and genomic medicine in Tunisia. Mol Genet Genomic Med 2018; 6:134-159. [PMID: 29663716 PMCID: PMC5902400 DOI: 10.1002/mgg3.392] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 03/07/2018] [Indexed: 01/19/2023] Open
Abstract
Genetics and genomic medicine in Tunisia.
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Tadmouri GO, Sastry KS, Chouchane L. Arab gene geography: From population diversities to personalized medical genomics. Glob Cardiol Sci Pract 2014; 2014:394-408. [PMID: 25780794 PMCID: PMC4355514 DOI: 10.5339/gcsp.2014.54] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 12/11/2014] [Indexed: 12/20/2022] Open
Abstract
Genetic disorders are not equally distributed over the geography of the Arab region. While a number of disorders have a wide geographical presence encompassing 10 or more Arab countries, almost half of these disorders occur in a single Arab country or population. Nearly, one-third of the genetic disorders in Arabs result from congenital malformations and chromosomal abnormalities, which are also responsible for a significant proportion of neonatal and perinatal deaths in Arab populations. Strikingly, about two-thirds of these diseases in Arab patients follow an autosomal recessive mode of inheritance. High fertility rates together with increased consanguineous marriages, generally noticed in Arab populations, tend to increase the rates of genetic and congenital abnormalities. Many of the nearly 500 genes studied in Arab people revealed striking spectra of heterogeneity with many novel and rare mutations causing large arrays of clinical outcomes. In this review we provided an overview of Arab gene geography, and various genetic abnormalities in Arab populations, including disorders of blood, metabolic, circulatory and neoplasm, and also discussed their associated molecules or genes responsible for the cause of these disorders. Although studying Arab-specific genetic disorders resulted in a high value knowledge base, approximately 35% of genetic diseases in Arabs do not have a defined molecular etiology. This is a clear indication that comprehensive research is required in this area to understand the molecular pathologies causing diseases in Arab populations.
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Affiliation(s)
| | - Konduru S Sastry
- Laboratory of Genetic Medicine and Immunology, Weill Cornell Medical College in Qatar, Qatar Foundation, Doha, Qatar
| | - Lotfi Chouchane
- Laboratory of Genetic Medicine and Immunology, Weill Cornell Medical College in Qatar, Qatar Foundation, Doha, Qatar
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7
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Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families. PLoS One 2013; 8:e72195. [PMID: 24039744 PMCID: PMC3770653 DOI: 10.1371/journal.pone.0072195] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 07/06/2013] [Indexed: 11/29/2022] Open
Abstract
Large genomic rearrangements (LGRs) in DNA-mismatch-repair (MMR) genes, particularly among MSH2 gene, are frequently involved in the etiology of Lynch syndrome (LS). The Multiplex Ligation and Probe Amplification assay (MLPA) is commonly used to identify such alterations. However, in most cases, the MLPA-identified alteration is not characterized at the molecular level, which might be important to identify recurrent alterations and to analyze the molecular mechanisms underlying these mutational events. Probands from a cohort of Lynch Syndrome families were screened for point mutation in MMR genes, subsequently the MLPA assay was used for LGR screening. The identified MLPA alteration was confirmed by cDNA, CGH-microarrays or massive parallel sequencing. In this study, we have delimited the region of 11 LGRs variants on MSH2 locus. Six of them were fully characterized the breakpoints and 9 of them were considered pathogenic. According to our data, LGR on MSH2 locus constituted the 10.8% (9 out of 83) of pathogenic germline alterations found in LS. The frequency of colorectal cancer (CRC) and endometrial cancer (EC) in LGR carriers was 55% and 11% respectively. Analysis of the breakpoint sequences revealed that in 3 cases, deletions appeared to originate from Alu-mediated recombination events. In the remaining cases, sequence alignment failed to detect microhomology around the breakpoints. The present study provides knowledge on the molecular characterization of MSH2 LGRs, which may have important implications in LS diagnosis and Genetic Counseling. In addition, our data suggests that nonhomologous events would be more frequently involved in the etiology of MSH2 LGRs than expected.
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Aissi S, Buisine MP, Zerimech F, Kourda N, Moussa A, Manai M, Porchet N. Somatic molecular changes and histo-pathological features of colorectal cancer in Tunisia. World J Gastroenterol 2013; 19:5286-5294. [PMID: 23983431 PMCID: PMC3752562 DOI: 10.3748/wjg.v19.i32.5286] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 05/14/2013] [Accepted: 07/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine correlations between family history, clinical features and mutational status of genes involved in the progression of colorectal cancer (CRC).
METHODS: Histo-pathological features and molecular changes [KRAS, BRAF and CTNNB1 genes mutations, microsatellite instability (MSI) phenotype, expression of mismatch repair (MMR) and mucin (MUC) 5AC proteins, mutation and expression analysis of TP53, MLH1 promoter hypermethylation analysis] were examined in a series of 51 unselected Tunisian CRC patients, 10 of them had a proven or probable hereditary disease, on the track of new tumoral markers for CRC susceptibility in Tunisian patients.
RESULTS: As expected, MSI and MMR expression loss were associated to the presence of familial CRC (75% vs 9%, P < 0.001). However, no significant associations have been detected between personal or familial cancer history and KRAS (codons 12 and 13) or TP53 (exons 4-9) alterations. A significant inverse relationship has been observed between the presence of MSI and TP53 accumulation (10.0% vs 48.8%, P = 0.0335) in CRC tumors, suggesting different molecular pathways to CRC that in turn may reflect different environmental exposures. Interestingly, MUC5AC expression was significantly associated to the presence of MSI (46.7% vs 8.3%, P = 0.0039), MMR expression loss (46.7% vs 8.3%, P = 0.0039) and the presence of familial CRC (63% vs 23%, P = 0.039).
CONCLUSION: These findings suggest that MUC5AC expression analysis may be useful in the screening of Tunisian patients with high risk of CRC.
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Evaluation of a new panel of six mononucleotide repeat markers for the detection of DNA mismatch repair-deficient tumours. Br J Cancer 2013; 108:2079-87. [PMID: 23652311 PMCID: PMC3670492 DOI: 10.1038/bjc.2013.213] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background: Microsatellite instability (MSI) is a molecular phenotype due to defective DNA mismatch repair (MMR) system. It is used to predict outcome of colorectal tumours and to screen tumours for Lynch syndrome (LS). A pentaplex panel composed of five mononucleotide markers has been largely recommended for determination of the MSI status. However, its sensitivity may be taken in default in occasional situations. The aim of the study was to optimise this panel for the detection of MSI. Methods: We developed an assay allowing co-amplification of six mononucleotide repeat markers (BAT25, BAT26, BAT40, NR21, NR22, NR27) and one polymorphic dinucleotide marker (D3S1260) in a single reaction. Performances of the new panel were evaluated on a cohort of patients suspected of LS. Results: We demonstrate that our assay is technically as easy to use as the pentaplex assay. The hexaplex panel shows similar performances for the identification of colorectal and non-MSH6-deficient tumours. On the other hand, the hexaplex panel has higher sensitivity for the identification of MSH6-deficient tumours (94.7% vs 84.2%) and MMR-deficient tumours other than colorectal cancer (92.9% vs 85.7%). Conclusion: The hexaplex panel could thus be an attractive alternative to the pentaplex panel for the identification of patients with LS.
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Contribution of large genomic rearrangements in Italian Lynch syndrome patients: characterization of a novel alu-mediated deletion. BIOMED RESEARCH INTERNATIONAL 2012; 2013:219897. [PMID: 23484096 PMCID: PMC3591251 DOI: 10.1155/2013/219897] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 11/20/2012] [Indexed: 11/18/2022]
Abstract
Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in the MLH1 and MSH2 genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in the MLH1, MSH2, and MSH6 genes. We identified a large novel deletion in the MSH2 gene, including exon 6 in one of the patients analysed (1.6% frequency). This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement within MSH2 gene and showed that large deletions or duplications in MLH1 and MSH2 genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.
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11
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Salem IH, Hsairi I, Mezghani N, Kenoun H, Triki C, Fakhfakh F. CAPN3 mRNA processing alteration caused by splicing mutation associated with novel genomic rearrangement of Alu elements. J Hum Genet 2011; 57:92-100. [PMID: 22158424 DOI: 10.1038/jhg.2011.129] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Recessive mutations of CAPN3 gene are reported to be responsible for limb girdle muscular dystrophy type 2A (LGMD2A). In all, 15-25% of intronic nucleotide changes identified in this gene were investigated by in silico analysis, but occasionally supported by experimental data or reported in some cases as a polymorphism. We report here genetic and transcriptional analyses in three Tunisian patients belonging to the same consanguineous family sharing the same mutation c.1194-9 A>G and Alu repeats insertion in intron 7 of CAPN3 gene. Reverse transcriptase-PCR experiments performed on total RNA from the patient's muscle biopsy showed retention of the eight last nucleotides of intron 9 in the CAPN3 transcript lacking the first seven exons. Our results provide evidence regarding the potential involvement of Alu elements in aberrant processing of pre-mRNA owing to the disruption of pre-existing intronic splicing regulatory elements. We also demonstrated variable mRNA alternative splicing among tissues and between LGMD2A patients. A deep intronic variation and rearrangement have been reported in the literature as causing genetic diseases in humans. However, this is the first report on a potential pathogenic CAPN3 gene mutation resulting from an Alu insertion.
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Affiliation(s)
- Ikhlass Hadj Salem
- Laboratoire de Génétique Moléculaire Humaine, Université de Sfax, Sfax, Tunisia.
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12
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Crépin M, Dieu MC, Lejeune S, Escande F, Boidin D, Porchet N, Morin G, Manouvrier S, Mathieu M, Buisine MP. Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility. Hum Mutat 2011; 33:180-8. [PMID: 21953887 DOI: 10.1002/humu.21617] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Accepted: 09/07/2011] [Indexed: 12/19/2022]
Abstract
Constitutional epimutations of DNA mismatch repair (MMR) genes have been recently reported as a possible cause of Lynch syndrome. However, little is known about their prevalence, the risk of transmission through the germline and the risk for carriers to develop cancers. In this study, we evaluated the contribution of constitutional epimutations of MMR genes in Lynch syndrome. A cohort of 134 unrelated Lynch syndrome-suspected patients without MMR germline mutation was screened for constitutional epimutations of MLH1 and MSH2 by quantitative bisulfite pyrosequencing. Patients were also screened for the presence of EPCAM deletions, a possible cause of MSH2 methylation. Tumors from patients with constitutional epimutations were extensively analyzed. We identified a constitutional MLH1 epimutation in two proband patients. For one of them, we report for the first time evidence of transmission to two children who also developed early colonic tumors, indicating that constitutional MLH1 epimutations are associated to a real risk of transgenerational inheritance of cancer susceptibility. Moreover, a somatic BRAF mutation was detected in one affected child, indicating that tumors from patients carrying constitutional MLH1 epimutation can mimic MSI-high sporadic tumors. These findings may have important implications for future diagnostic strategies and genetic counseling.
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Affiliation(s)
- Michel Crépin
- Oncologie et Génétique Moléculaires, Service de Biochimie et Biologie Moléculaire HMNO, CHRU de Lille, France
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Abstract
PURPOSE Lynch syndrome accounts for 2-4% of all colorectal cancer, and is mainly caused by germline mutations in the DNA mismatch repair genes. Our aim was to characterize the genetic mutation responsible for Lynch syndrome in an extensive Colombian family and to study its prevalence in Antioquia. METHODS A Lynch syndrome family fulfilling Amsterdam criteria II was studied by immunohistochemistry and by multiplex ligation-dependent probe amplification (MLPA). Results were confirmed by additional independent MLPA, Southern blotting, and sequencing. RESULTS Index case tumor immunohistochemistry results were MLH1-, MSH2+, MSH6+, and PMS2-. MLPA analysis detected a duplication of exons 12 and 13 of MLH1. This mutation was confirmed and characterized precisely to span 4219 base pairs. Duplication screening in this family led to the identification of six additional carriers and 13 noncarriers. We also screened 123 early-onset independent colorectal cancer cases from the same area and identified an additional unrelated carrier. CONCLUSION A novel duplication of exons 12 and 13 of the MLH1 gene was detected in two independent Lynch syndrome families from Colombia. A putative founder effect and prescreening Lynch syndrome Antioquia families for this specific mutation before thorough mismatch repair mutational screening could be suggested.
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Moussa SAB, Moussa A, Kourda N, Mezlini A, Abdelli N, Zerimech F, Najjar T, Jilani SB, Porchet N, Ayed FB, Manai M, Buisine MP. Lynch syndrome in Tunisia: first description of clinical features and germline mutations. Int J Colorectal Dis 2011; 26:455-67. [PMID: 21311894 DOI: 10.1007/s00384-010-1129-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/29/2010] [Indexed: 02/04/2023]
Abstract
PURPOSE High rates of early colorectal cancers (CRC) are observed in Tunisia suggesting genetic susceptibility. Nevertheless, up to now, no molecular study has been performed in the Tunisian population. In our research, we evaluated the clinical characteristics of Tunisian families suspected of Lynch syndrome and the contribution of DNA mismatch repair (MMR) genes. METHODS Thirty-one unrelated families suspected of Lynch syndrome were studied. Probands were tested for the presence of germline mutations in the MMR genes MLH1, MSH2, MSH6 and in MUTYH. Available tumours were analysed for microsatellite instability and expression of MMR proteins. Detailed family and medical histories were collected. RESULTS A total of 134 cancers were noted in the 31 families, the most frequent type of cancer corresponding to CRC (69%), followed by uterine cancer (7.5%). Germline mutations were identified in 11 (35.5%) families (six MSH2, five MLH1, including seven novel mutations), seven of which fulfilled the Amsterdam criteria (sensitivity, 63.6%; positive predictive value, 58.3%). Noteworthy, germline mutations were detected in 52.6% of male patients tested, but in only 8.3% of females (p = 0.02). Moreover, CRC were essentially left sided in families without detected mutation (p = 0.017). Ages of onset of cancers and tumour spectrum were very similar in families with or without MMR germline mutation, contrasting with previous studies performed in other populations. CONCLUSIONS MMR genes contribute significantly to CRC susceptibility in the Tunisian population. However, the cause of early CRC susceptibility remains unknown in most cases, especially in women and in patients with early left colon or rectal cancer.
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Affiliation(s)
- Sana Aissi-Ben Moussa
- Laboratoire de Biochimie et Biologie Moléculaire de Faculté des Sciences de Tunis, Tunis, Tunisia
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15
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16
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Belancio VP, Roy-Engel AM, Deininger PL. All y'all need to know 'bout retroelements in cancer. Semin Cancer Biol 2010; 20:200-10. [PMID: 20600922 PMCID: PMC2943028 DOI: 10.1016/j.semcancer.2010.06.001] [Citation(s) in RCA: 138] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2010] [Revised: 06/14/2010] [Accepted: 06/17/2010] [Indexed: 01/08/2023]
Abstract
Genetic instability is one of the principal hallmarks and causative factors in cancer. Human transposable elements (TE) have been reported to cause human diseases, including several types of cancer through insertional mutagenesis of genes critical for preventing or driving malignant transformation. In addition to retrotransposition-associated mutagenesis, TEs have been found to contribute even more genomic rearrangements through non-allelic homologous recombination. TEs also have the potential to generate a wide range of mutations derivation of which is difficult to directly trace to mobile elements, including double strand breaks that may trigger mutagenic genomic rearrangements. Genome-wide hypomethylation of TE promoters and significantly elevated TE expression in almost all human cancers often accompanied by the loss of critical DNA sensing and repair pathways suggests that the negative impact of mobile elements on genome stability should increase as human tumors evolve. The biological consequences of elevated retroelement expression, such as the rate of their amplification, in human cancers remain obscure, particularly, how this increase translates into disease-relevant mutations. This review is focused on the cellular mechanisms that control human TE-associated mutagenesis in cancer and summarizes the current understanding of TE contribution to genetic instability in human malignancies.
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Affiliation(s)
- Victoria P. Belancio
- Tulane University, Department of Structural and Cellular Biology, School of Medicine, Tulane Cancer Center and Tulane Center for Aging
| | - Astrid M. Roy-Engel
- Tulane University, Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane Cancer Center
| | - Prescott L. Deininger
- Tulane University, Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane Cancer Center
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Konkel MK, Batzer MA. A mobile threat to genome stability: The impact of non-LTR retrotransposons upon the human genome. Semin Cancer Biol 2010; 20:211-21. [PMID: 20307669 PMCID: PMC2925057 DOI: 10.1016/j.semcancer.2010.03.001] [Citation(s) in RCA: 130] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2010] [Revised: 03/04/2010] [Accepted: 03/16/2010] [Indexed: 02/06/2023]
Abstract
It is now commonly agreed that the human genome is not the stable entity originally presumed. Deletions, duplications, inversions, and insertions are common, and contribute significantly to genomic structural variations (SVs). Their collective impact generates much of the inter-individual genomic diversity observed among humans. Not only do these variations change the structure of the genome; they may also have functional implications, e.g. altered gene expression. Some SVs have been identified as the cause of genetic disorders, including cancer predisposition. Cancer cells are notorious for their genomic instability, and often show genomic rearrangements at the microscopic and submicroscopic level to which transposable elements (TEs) contribute. Here, we review the role of TEs in genome instability, with particular focus on non-LTR retrotransposons. Currently, three non-LTR retrotransposon families - long interspersed element 1 (L1), SVA (short interspersed element (SINE-R), variable number of tandem repeats (VNTR), and Alu), and Alu (a SINE) elements - mobilize in the human genome, and cause genomic instability through both insertion- and post-insertion-based mutagenesis. Due to the abundance and high sequence identity of TEs, they frequently mislead the homologous recombination repair pathway into non-allelic homologous recombination, causing deletions, duplications, and inversions. While less comprehensively studied, non-LTR retrotransposon insertions and TE-mediated rearrangements are probably more common in cancer cells than in healthy tissue. This may be at least partially attributed to the commonly seen global hypomethylation as well as general epigenetic dysfunction of cancer cells. Where possible, we provide examples that impact cancer predisposition and/or development.
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Affiliation(s)
- Miriam K. Konkel
- Department of Biological Sciences, Biological Computation and Visualization Center, Louisiana State University, 202 Life Sciences Building, Baton Rouge, Louisiana 70803, USA
| | - Mark A. Batzer
- Department of Biological Sciences, Biological Computation and Visualization Center, Louisiana State University, 202 Life Sciences Building, Baton Rouge, Louisiana 70803, USA
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McCabe MT, Powell DR, Zhou W, Vertino PM. Homozygous deletion of the STK11/LKB1 locus and the generation of novel fusion transcripts in cervical cancer cells. CANCER GENETICS AND CYTOGENETICS 2010; 197:130-41. [PMID: 20193846 PMCID: PMC2837085 DOI: 10.1016/j.cancergencyto.2009.11.017] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/10/2009] [Revised: 11/14/2009] [Accepted: 11/25/2009] [Indexed: 01/20/2023]
Abstract
The STK11/LKB1 gene encodes a ubiquitously expressed serine/threonine kinase that is mutated in multiple sporadic cancers including non-small cell lung carcinomas, pancreatic cancers, and melanomas. LKB1 plays a role in multiple cellular functions including cell growth, cell cycle progression, metabolism, cell polarity, and migration. To date, only a limited number of studies have assessed the status of LKB1 in cervical cancers. Herein, we investigate DNA methylation, DNA mutation, and transcription at the LKB1 locus in cervical cancer cell lines. We identified homozygous deletions of 25-85kb in the HeLa and SiHa cell lines. Deletion breakpoint analysis in HeLa cells revealed that the deletion resulted from an Alu-recombination-mediated deletion (ARMD) and generated a novel LKB1 fusion transcript driven by an uncharacterized CpG island promoter located approximately 11kb upstream of LKB1. Although the homozygous deletion in SiHa cells removes the entire LKB1 gene and portions of the neighboring genes SBNO2 and c19orf26, this deletion also generates a fusion transcript driven by the c19orf26 promoter and composed of both c19orf26 and SBNO2 sequences. Further analyses of public gene expression and mutation databases suggest that LKB1 and its neighboring genes are frequently dysregulated in primary cervical cancers. Thus, homozygous deletions affecting LKB1 in cervical cancers may generate multiple fusion transcripts involving LKB1, SBNO2, and c19orf26.
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Affiliation(s)
- Michael T. McCabe
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322
| | - Doris R. Powell
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322
| | - Wei Zhou
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322
| | - Paula M. Vertino
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322
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