Identification of genetic variants for clinical management of familial colorectal tumors
| العنوان: | Identification of genetic variants for clinical management of familial colorectal tumors |
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| المؤلفون: | Monika Morak, Eivind Hovig, Elke Holinski-Feder, Sigve Nakken, Anke M. Nissen, Mev Dominguez-Valentin, Hélène Tubeuf, Daniel Vodak, Per Olaf Ekstrøm, Alexandra Martins, Pål Møller |
| المساهمون: | Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital of the Ludwig-Maximilian-University Munich, Medizinische Klinik â€' Innenstadt, Lehrstuhl für Endokrinologie/Diabetologie, University Hospital of the Ludwig-Maximilians University, Génétique du cancer et des maladies neuropsychiatriques (GMFC) |
| المصدر: | BMC Medical Genetics BMC Medical Genetics, BioMed Central, 2018, 19 (1), ⟨10.1186/s12881-018-0533-9⟩ BMC Medical Genetics, Vol 19, Iss 1, Pp 1-19 (2018) |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Adult, Male, lcsh:Internal medicine, lcsh:QH426-470, [SDV]Life Sciences [q-bio], RNA Splicing, MAP Kinase Kinase Kinase 1, RNA splicing mutations, Biology, DNA Mismatch Repair, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene panel testing, lcsh:RC31-1245, Gene, CHEK2, Receptor, Notch3, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Norway, Genetic Variation, Exons, Sequence Analysis, DNA, Amplicon, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Human genetics, Lynch syndrome, 3. Good health, lcsh:Genetics, Checkpoint Kinase 2, 030104 developmental biology, 030220 oncology & carcinogenesis, RNA splicing, DNA mismatch repair, Female, Colorectal Neoplasms, Minigene, Research Article |
| الوصف: | Background The genetic mechanisms for families who meet the clinical criteria for Lynch syndrome (LS) but do not carry pathogenic variants in the mismatch repair (MMR) genes are still undetermined. We aimed to study the potential contribution of genes other than MMR genes to the biological and clinical characteristics of Norwegian families fulfilling Amsterdam (AMS) criteria or revised Bethesda guidelines. Methods The Hereditary Cancer Biobank of the Norwegian Radium Hospital was interrogated to identify individuals with a high risk of developing colorectal cancer (CRC) for whom no pathogenic variants in MMR genes had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by using our in-house designed TruSeq amplicon-based assay for targeted sequencing. RNA splicing- and protein-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as likely to affect splicing were experimentally analyzed by resorting to minigene assays. Results We identified a patient who met the revised Bethesda guidelines and carried a likely pathogenic variant in CHEK2 (c.470 T > C, p.I157T). In addition, 25 unique VUS were identified in 18 individuals, of which 2 exonic variants (MAP3K1 c.764A > G and NOTCH3 c.5854G >A) were analyzed in the minigene splicing assay and found not to have an effect on RNA splicing. Conclusions Among high-risk CRC patients that fulfill the AMS criteria or revised Bethesda guidelines, targeted gene sequencing identified likely pathogenic variant and VUS in other genes than the MMR genes (CHEK2, NOTCH3 and MAP3K1). Our study suggests that the analysis of genes currently excluded from routine molecular diagnostic screens may confer cancer susceptibility. |
| تدمد: | 1471-2350 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c7bb28d8f5e4adb2af795c1e1bc442f5Test https://pubmed.ncbi.nlm.nih.gov/29458332Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c7bb28d8f5e4adb2af795c1e1bc442f5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14712350 |
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