Germline RET variants underlie a subset of paediatric osteosarcoma
Autor: | Marco Francesco Morini, Claudia Blattmann, Eva K. Roth, Mandy L. Ballinger, David Thomas, Karl Heinimann, Ian Tomlinson, Andreas E. Kulozik, Michaela Nathrath, Monika Kovacova, Baptiste Ameline, Sebastian Ribi, Wolfgang Hartmann, Michal Kovac, Connor Woolley, Daniel Baumhoer, Stefan S. Bielack |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
medicine.medical_specialty Somatic cell Biology medicine.disease Germline Thyroid carcinoma 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Germline mutation 030220 oncology & carcinogenesis Molecular genetics Genetics medicine Cancer research Osteosarcoma Kinase activity Multiple endocrine neoplasia neoplasms Genetics (clinical) |
Zdroj: | Journal of Medical Genetics. 58:20-24 |
ISSN: | 1468-6244 0022-2593 |
DOI: | 10.1136/jmedgenet-2019-106734 |
Popis: | BackgroundAlthough considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone.Methods and resultsWe followed here a coincidental finding in a multiple endocrine neoplasia family in which a 32-year-old patient carrying a germline pathogenic RET mutation developed an osteosarcoma 2 years after the resection of a medullary thyroid carcinoma. Sequencing analysis of additional 336 patients with osteosarcoma led to the identification of germline activating mutations in the RET proto-oncogene in three cases and somatic amplifications of the gene locus in five matched tumours (4%, n=5/124 tumours). Functional analysis of the pathogenic variants together with an integrative analysis of osteosarcoma genomes confirmed that the mutant RET proteins couple functional kinase activity to dysfunctional ligand binding. RET mutations further co-operated with alterations in TP53 and RB1, suggesting that osteosarcoma pathogenesis bears reminiscence to the stepwise model of medullary thyroid carcinoma.ConclusionsAfter Li-Fraumeni-predisposing mutations in TP53, RET becomes the second most mutated cancer-predisposing gene in the germline of patients with osteosarcoma. Hence, early identification of RET mutation carriers can help to identify at-risk family members and carry out preventive measures. |
Databáze: | OpenAIRE |
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