Somatic mosaics in hereditary tumor predisposition syndromes |
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| Affiliation: | 1. MGZ - Medical Genetics Center, Germany;2. Arbeitsgruppe Erbliche Gastrointestinale Tumore, Medizinische Klinik und Poliklinik IV – Campus Innenstadt, Klinikum der Universität München, Germany;3. Center for Medical Genetics, Ghent University Hospital, Belgium;4. CRIG (Cancer Research Institute Ghent) and Department of Biomolecular Medicine, Ghent University, Belgium;1. IRCCS, Istituto delle Scienze Neurologiche di Bologna, UOC Neuropsichiatria dell''età pediatrica, Bologna, Italy;2. Department of Medical Sciences Pediatric Section, University of Ferrara, Italy;3. Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy;4. Università di Padova, Italy;5. IRCCS, Istituto delle Scienze Neurologiche di Bologna, UOC Neuroradiologia, Bologna, Italy;6. IRCCS, Istituto delle Scienze Neurologiche di Bologna, UOC Medicina Riabilitativa, Bologna, Italy;7. Robert Hollman Foundation, Padova, Italy;1. Department of Clinical Genetics, Ninewells Hospital, Dundee, Scotland, UK;2. High Risk and Cancer Prevention Unit, Vall D’Hebron Institute of Oncology, Barcelona, Spain;3. Medical Oncology Department, Vall D’Hebron Hospital, Barcelona, Spain;1. Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA;2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;3. Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA;4. Harvard Medical School, Boston, MA, USA;5. Department of Pathology, Brigham and Women''s Hospital, Boston, MA, USA;6. Department of Radiology, Brigham and Women''s Hospital, Boston, MA, USA;7. Division of Genetics, Department of Medicine, Brigham and Women''s Hospital, Boston, MA, USA;1. Genomics Laboratory, Department of Clinical Analyses. Clinical University Hospital Virgen Arrixaca, Spain;2. Department of Medical Oncology, Clinical University Hospital Virgen Arrixaca, Spain;3. Department of Medical Oncology, Clinical University Hospital Morales Meseguer, Spain;1. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands;2. Department of Paediatric Neurology, Radboud University Medical Center, Nijmegen, the Netherlands;3. Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands;4. Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands |
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| Abstract: | Historically, it is estimated that 5–10% of cancer patients carry a causative genetic variant for a tumor predisposition syndrome. These conditions have high clinical relevance as they are actionable regarding risk-specific surveillance, predictive genetic testing, reproductive options, and – in some cases – risk reducing surgery or targeted therapy. Every individual is born with on average 0.5–1 exonic mosaic variants prevalent in single or multiple tissues. Depending on the tissues affected, mosaic conditions can abrogate the clinical phenotype of a tumor predisposition syndrome and can even go unrecognized, because it can be impossible or difficult to detect them with routine genetic testing in blood/leucocytes. On the other hand, it is estimated that at least 4% of presumed de novo variants are the result of low-level mosaicism (variant allele frequency <10%) in a parent, while around 7% are true mosaic variants with a higher variant allele frequency, which can sometimes be confused for heterozygous variants. Clonal hematopoiesis however can simulate a mosaic tumor predisposition in genetic diagnostics and has to be taken into account, especially for TP53 variants.Depending on the technique, variant allele frequencies of 2–3% can be detected for single nucleotide variants by next generation sequencing, copy number variants with variant allele frequencies of 5–30% can be detected by array-based technologies or MLPA.Mosaic tumor predisposition syndromes are more common than previously thought and may often remain undiagnosed. The clinical suspicion and diagnostic procedure for several cases with mosaic tumor predisposition syndromes are presented. |
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| Keywords: | Tumor predisposition syndromes Somatic mosaicism |
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