Background Although 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 results We 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.
Conclusions After 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.
- molecular genetics
- paediatric oncology
- calcium and bone
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KH and DB are joint supervised authors.
CW and SR contributed equally.
Contributors MiK, SR and MoK performed bioinformatics analyses. SR, CW, BA, MM and ER performed laboratory experiments. MiK, DB, CB, AK, WH, SB, MLB, DMT and MN were responsible for patients’ management and/or generation of NGS sequencing data. WH and KH supervised the technical replication phase. MiK, IT, KH and DB wrote the manuscript.
Funding The results published here are also in part based on data generated by the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative managed by the NCI. MiK, SR and DB were supported by the Gertrude von Meissner-Stiftung, the Foundation of the Basel Bone Tumor Reference Centre, the Gedächtnis-Stiftung Susy Rückert, the Nora van Meeuwen- Häfliger Stiftung and the Stiftung für krebskranke Kinder Regio Basiliensis.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.