Identification of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins
| Autor: | M Mahmoudi, Samir Boubaker, Amira Jaballah-Gabteni, Haifa Tounsi, Mousaddak Azzouz, Hamza Dallali, Hamza Yaiche, Sahar Elouej, Maria Kabbage, Ines Ben Ayed, Lamine Hamzaoui, Mouna Medhioub, Sonia Abdelhak, Afifa Maaloul, Yosr Hamdi, Nadia Ben Jemii, Najla Mezghani |
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| Přispěvatelé: | Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mohamed Tahar Maamouri Hospital [Tunisia], This work was supported by the Tunisian Ministry of Public Health, the Tunisian Ministry of Higher Education and Scientific Research (LR16IPT05)., The authors are extremely grateful to the patients whose participation made this work possible, to Dr. Houcemeddine Othman who participated to the in silico prediction and to Dr. Monia Ardhaoui who participated to the figure revision. |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine [SDV]Life Sciences [q-bio] lcsh:Medicine Lynch syndrome I medicine.disease_cause DNA Mismatch Repair DRGs 0302 clinical medicine MESH: Germ-Line Mutation PMS2 MMR genes Genetics Mutation MESH: Middle Aged MESH: Genetic Testing MESH: Polymorphism Single Nucleotide MESH: Genetic Predisposition to Disease MESH: Colorectal Neoplasms Hereditary Nonpolyposis General Medicine Middle Aged Penetrance Lynch syndrome Pedigree CRC 3. Good health MutS Homolog 2 Protein MESH: DNA Mismatch Repair 030220 oncology & carcinogenesis DNA mismatch repair MESH: Tunisia Tunisian family Adult congenital hereditary and neonatal diseases and abnormalities Tunisia MESH: Mutation MESH: Pedigree Biology Polymorphism Single Nucleotide MESH: MutS Homolog 2 Protein General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Germline mutation Diseases in Twins medicine Humans Family Genetic Predisposition to Disease Genetic Testing MESH: Family Germ-Line Mutation MESH: Humans Research lcsh:R MESH: Adult medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis MESH: Male digestive system diseases MSH6 030104 developmental biology MSH2 MESH: Diseases in Twins |
| Zdroj: | Journal of Translational Medicine, Vol 17, Iss 1, Pp 1-13 (2019) Journal of Translational Medicine Journal of Translational Medicine, BioMed Central, 2019, 17 (1), pp.212. ⟨10.1186/s12967-019-1961-9⟩ |
| ISSN: | 1479-5876 |
| Popis: | Background Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome, characterized by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. Despite several genetic variations that have been identified in various populations, the penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether, besides pathogenic mutations, environment and low penetrance genetic risk factors may result in phenotype modification in a Tunisian LS family. Patients and methods A Tunisian family with strong colorectal cancer (CRC) history that fulfill the Amsterdam I criteria for the diagnosis of Lynch syndrome was proposed for oncogenetic counseling. The index case was a man, diagnosed at the age of 33 years with CRC. He has a monozygotic twin diagnosed at the age of 35 years with crohn disease. Forty-seven years-old was the onset age of his paternal uncle withCRC. An immunohistochemical (IHC) labeling for the four proteins (MLH1, MSH2, MSH6 and PMS2) of the MisMatchRepair (MMR) system was performed for the index case. A targeted sequencing of MSH2, MLH1 and a panel of 85 DNA repair genes was performed for the index case and for his unaffected father. Results The IHC results showed a loss of MSH2 but not MLH1, MSH6 and PMS2 proteins expression. Genomic DNA screening, by targeted DNA repair genes sequencing, revealed an MSH2 pathogenic mutation (c.1552C>T; p.Q518X), confirmed by Sanger sequencing. This mutation was suspected to be a causal mutation associated to the loss of MSH2 expression and it was found in first and second degree relatives. The index case has smoking and alcohol consumption habits. Moreover, he harbors extensive genetic variations in other DNA-repair genes not shared with his unaffected father. Conclusion In our investigated Tunisian family, we confirmed the LS by IHC, molecular and in silico investigations. We identified a novel pathogenic mutation described for the first time in Tunisia. These results come enriching the previously reported pathogenic mutations in LS families. Our study brings new arguments to the interpretation of MMR expression pattern and highlights new risk modifiers genes eventually implicated in CRC. Twins discordance reported in this work underscore that disease penetrance could be influenced by both genetic background and environmental factors. Electronic supplementary material The online version of this article (10.1186/s12967-019-1961-9) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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