Germline RET variants underlie a subset of paediatric osteosarcoma

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.

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Genetic and Clinical Features of Medullary Thyroid Carcinoma: The Experience of a Single Center in Costa Rica

Journal of Cancer Epidemiology ◽

10.1155/2016/9637173 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Javier Calvo ◽

Gabriel Torrealba ◽

Adriana Sáenz ◽

Carlos Santamaría ◽

Estela Morera ◽

...

Keyword(s):

Costa Rica ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Case Series ◽

Mean Value ◽

Single Center ◽

Medullary Thyroid ◽

Activating Mutations ◽

Case Series Report ◽

Sporadic Disease

Background. Activating mutations in the RET gene leads to medullary thyroid carcinoma (MTC). Guidelines encourage performing RET analysis in subjects with hereditary and sporadic disease. Materials and Methods. Design. Observational, case series report study. Patients. Subjects diagnosed with MTC, with a thyroidectomy performed in a single center in Costa Rica between the years 2006 and 2015. Diagnosis and Follow-Up. Pre- and postoperative calcitonin, RET mutation, and neck ultrasound and tomography were obtained. Results. 21 subjects with histological diagnosis of MTC were followed up. The average age at diagnosis was 52.0 ± 15.7 years. The preoperative mean value of calcitonin was 1340 ± 665 pg/mL. Evidence of RET mutation was found in 26.3% of the patients, with only 2 of them grouped in the same kindred. We found statistically significant differences in mean ages between mutated (38.4 ± 20.2 y) versus nonmutated RET gene (54.6 ± 11.8 y, p=0.04). There were no significant differences regarding tumor size, metastases, and surgical reintervention. Conclusions. We report the results of RET mutation analysis in subjects with MTC in a single center of Costa Rica. The availability of this tool increases the probability of identifying familial MTC, with the benefit of detecting affected subjects and their relatives at an earlier age.

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Characterization of the RET protooncogene transmembrane domain mutation S649L associated with nonaggressive medullary thyroid carcinoma.

Acta Endocrinologica ◽

10.1530/eje-07-0817 ◽

2008 ◽

Vol 158 (6) ◽

pp. 811-816 ◽

Cited By ~ 25

Author(s):

Mario Colombo-Benkmann ◽

Zhenpeng Li ◽

Burkhard Riemann ◽

Karin Hengst ◽

Hermann Herbst ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Kinase Activity ◽

Transmembrane Domain ◽

Late Onset ◽

Cell Hyperplasia ◽

Nih3t3 Cells ◽

Medullary Thyroid ◽

Gene Carriers

ContextFor rare and novelRETmutations associated with hereditary medullary thyroid carcinoma (MTC), clinical and functional studies are needed to classify theRETmutation into one of the three clinical risk groups.ObjectiveWe analyzed proliferative properties and clinical implications associated with theRETprotooncogene transmembrane domain mutation S649L.DesignThe transforming potential and mitogenic properties of S649L mutation were investigated clinically and by evaluating kinase activity, cell proliferation, and colony formation.PatientsFifteen individuals from five kindreds were identified as carriers of aRETprotooncogene mutation in exon 11 codon 649 (TCGSer→TTGLeu). In two out of five index patients, a secondRETmutation (C634W or V804L) was detected.ResultsEight gene carriers were operated on. Histology revealed MTC and C-cell hyperplasia in three index and three screening patients respectively. In all other gene carriers (aged 41–64 years), calcitonin levels were in the normal range, and pentagastrin-stimulated calcitonin levels were <100 pg/ml. Therefore, thyroidectomy had not yet been performed. In one index patient carrying the S649L mutation, hyperparathyroidism was confirmed histologically.RETS649L-expressing NIH3T3 cells exhibited a clear increase of phosphotyrosine and proliferation rate when compared with parental NIH3T3 cells but a significantly lower kinase activity and cell growth rate when compared withRETC634R-expressing cells. When compared withRETC634R, the S649L mutant showed moderate transforming potential with small-sized colonies.ConclusionsOur clinical and in vitro findings indicate that the transmembraneRETS649L mutation is associated with late-onset non-aggressive disease. Recommendations for prophylactic thyroidectomy should be individualized depending on stimulated calcitonin levels.

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