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Purpose: Aims of this study were to investigate the prevalence of TP53and TERTmutations in Medullary Thyroid carcinoma (MTC) and their role in inducing aggressiveness in positive cases. Methods: We performed a literature search in PubMed to identify studies investigating the prevalence of TERTand TP53mutations in MTC. We also included data on MTC cases (n = 193) obtained at our center and unpublished. The in-silico pathogenicity of the TP53mutations has been evaluated by predictor tools. Results: We identified a total of 25 and 11 published papers: all together 1280 cases have been investigated for the presence of TP53mutations and 974 for TERTpromoter mutation. Twenty-five out of 1280 (2%) cases had a TP53mutation while only 3/974 MTC cases (0.3%) have been found to be positive for TERTpromoter mutations. Among all, we identified 19 different TP53 mutations that in 12 cases were demonstrated to have an in silico predicted high pathogenic role and a high impact on protein function. Three non-sense and 4 probably not damaging mutations were also reported. The pathogenic role of the TERTpromoter mutations has been previously in vitro determined. No correlation between TP53and/or TERTmutations and aggressiveness of MTC has been demonstrated. Conclusion: The prevalence of TP53and TERTpromoter mutations is very low in MTC. The reported mutations are pathogenic in the majority of cases. Because of their rarity it is not possible to clarify if they play or not a role in the pathogenesis and/or aggressiveness of this specific thyroid tumor.

Purpose: Thyroid carcinoma (TC) is a rare neoplasia of the endocrine system and account for about 2–3% of all human tumors. According to their cell origin and histological features, different histotypes of thyroid carcinoma are described. Genetic alterations involved in the pathogenesis of thyroid cancer have been described and it has been shown that alterations of the RETgene are common events in all TC hystotypes. Aim of this review is to give an overview of the relevance of RETalterations in TC and to provide indications, timing and methodologies, for RETgenetic analysis. Methods: A revision of the literature has been performed and indications for the experimental approach for the RETanalysis have been reported. Conclusions: The analysis of RETmutations in TC has a very important clinical relevance for the early diagnosis of the hereditary forms of MTC, for the follow-up of TC patients and for the identification of those cases that can benefit from a specific treatment able to inhibit the effect of mutated RET.

Purpose: The 8th edition of the American Joint Committee on Cancer (AJCC) staging led to a significant downstaging of well differentiated thyroid cancer patients. However, some patients who had been downstaged still experienced death. By using data from the thyroid cancer dataset of The Cancer Genome Atlas (TCGA), we aimed to find molecular features that could improve survival prediction. Methods: TCGA data were downloaded from cBioPortal. Restaging of cases was performed according to the pathological reports. Results: Out of 496 cases, 204 (41.1%) were downstaged, and the proportion of deaths increased in stages III and IV. TERTpromoter mutations were no longer enriched in stage IV only, but significantly redistributed also in stages II and III. TERTmutation was the only alteration predictive of poor survival; however, in this series it was not independent from the AJCC staging. Five proteins (4E-BP1_pT70, Chk1_pS345, Snail, STAT5 alpha and PAI-1) were significantly associated with survival, and their use as a panel refined the risk stratification independently from the AJCC staging, with a hazard ratio for a positive result of 21.2 (95%CI 3.7–122.2, P= 0.0006). Conclusions: In the TCGA series, the proportion of deaths is in line with the expected survival of the latest AJCC staging, with a neat separation of risk among stages. Nevertheless, the use of protein expression can be useful in refining the stratification. Finally, after the restaging, a considerable number of tumors with TERTmutations will be allocated in lower stages; hence, dedicated studies should define the prognostic usefulness of these mutations in low-stage diseases.

We investigated the expression of RET9and RET51isoforms in medullary (MTC), papillary (PTC) thyroid carcinoma, normal thyroid tissues, and pheochromocytoma (PHEO) to verify if these isoforms are present also in follicular thyroid cell-derived tissues, and if there is a differential expression of RET9and RET51in MTC. Nineteen patients with MTC, 18 patients with PTC, 18 samples of contralateral normal thyroid tissues, and 5 cases of PHEO were included in this study. RETisoform expression was studied by real-time RT-PCR. All MTCs and PHEOs were positive for RET9and RET51. Fourteen/eighteen (77.7%) PTC cases were positive for RET9and/or RET51, and four were positive for only one of the genes. In normal thyroid tissues, 3/18 (16.7%) cases were negative for both isoforms, 4/18 (22.2%) were positive for both, and 11/18 (61.1%) were positive for only one. RETisoforms were expressed at different levels in MTC, PHEO, PTC, and normal thyroid tissues: RET9expression was higher in PHEO than in MTC, PTC, and normal thyroid tissues. RET9expression was also higher in MTC than in PTC and normal thyroid tissues. No difference was observed between PTC and normal thyroid tissues. A similar pattern of expression was observed for RET51. In addition, RET51was significantly more expressed than RET9in MTC, while RET9was the predominant isoform in PHEO. Our study documented the expression of the RET9and RET51isoforms in normal thyroid and PTC tissues. RET9and RET51isoforms were also present in MTC and PHEO. RET51expression was higher than RET9expression in MTC, while there was no difference in the expression of these two isoforms in PTC and normal thyroid tissues. RET9was more highly expressed than RET51in PHEOs.