Primary hyperparathyroidism (PHPT) caused by parathyroid tumours is mostly sporadic, with a genetic cause identified in 5–10

PurposeThe EIF1AX gene was recently described as a new thyroid cancer-related gene. Its mutations were mainly reported in poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC), but also in well-differentiated thyroid cancer (WDTC) and in benign thyroid lesions, although less frequently. Our aim was to address whether EIF1AX mutations are present in the different stages of thyroid tumourigenesis (from hyperplasia to well-differentiated and to poorly differentiated/undifferentiated lesions), and to clarify its role in this process.MethodsWe analysed the EIF1AX gene in a series of 16 PDTC and ATC cases with coexistent well-differentiated regions and/or benign lesions. In EIF1AX mutant cases we also assessed the presence of RAS genes mutations. ResultsWe identified the mutation p.Ala113_splice in the EIF1AX gene in two PDTCs (neither present in the well-differentiated counterparts nor in the benign areas). One of these tumours also evidenced the mutation p.Glu61Arg in NRAS in both poorly and well-differentiated regions, further suggesting that the EIF1AX p.Ala113_splice mutation could be associated with tumoural progression. In another patient we did not find any EIF1AX alteration in the PDTC component, but we detected the EIF1AX p.Gly6_splice mutation in the PTC area (both regions were RAS wild-type). This mutation did not seem to be related with dedifferentiation.ConclusionsAccording to our results, distinct mutations on EIF1AX may be related to different phenotypes/behaviours. Despite being a small series, which reflects the difficulty in retrieving PDTC and ATC surgical samples with well-differentiated and/or benign areas, our study may provide new insights into thyroid cancer tumourigenesis and dedifferentiation.

Anaplastic thyroid carcinomas (ATCs) are non-responsive to multimodal therapy, representing one of the major challenges in thyroid cancer. Previously, our group has shown that genes involved in cell cycle are deregulated in ATCs, and the most common mutations in these tumours occurred in cell proliferation and cell cycle related genes, namely TP53, RAS, CDKN2A and CDKN2B, making these genes potential targets for ATCs treatment. Here, we investigated the inhibition of HRAS by tipifarnib (TIP) and cyclin D-cyclin-dependent kinase 4/6 (CDK4/6) by palbociclib (PD), in ATC cells.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Activating germline mutations in the RET proto-oncogene are responsible for about 98 % of the familial forms of medullary thyroid carcinoma (MTC), which represent 25 % of all MTC cases. The search for germline mutations in this gene is important for the recognition of hereditary forms of MTC and further identification of at-risk relatives who may benefit from early clinical intervention. Genotype-phenotype correlations are well established for most disease-causing RET mutations, allowing risk stratification. The association of a new RET variant with the MTC phenotype and familial predisposition requires the assessment of its functional and clinical significance. The aim of this study was to evaluate the oncogenic potential of two newly identified RET germline variants associated with late-onset MTC. In vitro functional assays were designed to address the transforming potential of novel RET variants, through their expression in non-transformed cells, and comparing their effect with wild-type RET. The new variants were identified in codons 515 (p.C515W) and 636 (p.T636M) located, respectively, in exons 8 and 11, thus resulting in amino acid substitutions in the extracellular region of the tyrosine kinase receptor RET. Through functional assays, we observed increased cell growth and proliferation, loss of contact inhibition, and a stimulation of cell migration, suggesting that these new RET variants hold some relevant transforming potential. The transforming potential of these novel RET variants was of low-grade, when compared to that of RET MEN2A-causing mutation p.C634R, probably explaining the mild phenotype characterized by late onset and low clinical aggressiveness.

Twenty-five percent of medullary thyroid cancers (MTC) are familial and inherited as an autosomal dominant trait. Three different phenotypes can be distinguished: multiple endocrine neoplasia (MEN) types 2A and 2B, in which the MTC is associated with other endocrine neoplasias, and familial MTC (FMTC), which occurs in isolation. The discovery that germline RET oncogene activating mutations are associated with 95-98% of MEN 2/FMTC syndromes and the availability of genotyping to identify mutations in affected patients and their relatives has revolutionized the diagnostic and therapeutic strategies available for the management of these patients. All patients with MTC, both those with a positive familial history and those apparently sporadic, should be submitted to RET genetic screening. Once an RET mutation has been confirmed in an index patient, first-degree relatives should be screened rapidly to identify the 50% who inherited the mutation and are therefore at risk for development of MTC. Relatives in whom no RET mutation is identified can be reassured and discharged from further follow-up, whereas RET-positive subjects (i.e. gene carriers) must be investigated and a therapeutic strategy initiated. These guideline recommendations are derived from the most recent studies identifying phenotype-genotype correlations following the discovery of causative RET gene mutations in MEN 2 eighteen years ago. Three major points will be discussed: (a) identification of patients and relatives who should have genetic screening for RET mutations, (b) management of asymptomatic gene carriers, and (c) ethics.

Maria Alevizaki, Athens Ana Aranda, Madrid Rebecca Bahn, Rochester, Minn. Paul Banga, London Luigi Bartalena, Varese Bernadette Biondi, Naples Anita Boelen, Amsterdam Georg Brabant, Lubeck Henning Dralle, Halle Murat Erdogan, Ankara Creswell J. Eastman, Westmead, N.S.W. Valentin Fadeyev, Moscow Ulla Feldt-Rasmussen, Copenhagen Laszlo Hegedus, Odense George J. Kahaly, Mainz Rui Maciel, São Paolo Ana Luiza Maia, Porto Alegre Jens Mittag, Stockholm Ralf Paschke, Leipzig Simon Pearce, Newcastle-upon-Tyne Robin Peeters, Rotterdam Kris Poppe, Bruxelles Samuel Refetoff , Chicago, Ill. Jacques Samarut, Lyon Pilar Santisteban, Madrid YoungKee Shong, Seoul Jan Smit, Leiden Mark Vanderpump, London Th eo Visser, Rotterdam Paolo Vitti, Pisa Graham Williams, London Shunichi Yamashita, Nagasaki Mariastella Zannini, Naples Luca Persani, Milan (Translational Th yroidology)