Our 20-year study demonstrated that RET genetic screening is highly specific and sensitive, and it allows the reclassification as hereditary of apparently sporadic cases and the identification of GC who require an adequate follow-up. We confirmed that FMTC is the most prevalent MEN 2 syndrome and that it is strongly correlated with noncysteine RET mutations. According to these findings, a new paradigm of follow-up of hereditary MTC cases might be considered in the next future.

This study showed a high prevalence of somatic mutations in advanced and metastatic MTCs. mutations were present in a small percentage of cases and mutually exclusive with mutations. In a small number of cases, more than one mutation was present in the same tissue. double mutations and, to a lesser extent, also complex mutations showed a worse outcome.

To our knowledge, this is the first study analyzing a possible involvement of RET, BRAF and RAS oncogene mutations in PTC/MTC. These data clearly suggest that the classical activating mutations of the oncogenes commonly involved in the pathogenesis of PTC and MTC may not be responsible for their simultaneous occurrence.

PurposeMedullary Thyroid Cancer (MTC) whose pathogenesis is strictly related to RET proto-oncogene alterations, has been shown to have a heterogenic RET mutation profile in subpopulations of MTC. The aim of our study was to investigate the RET somatic mutation profile in primary MTC and in the corresponding metastatic tissues in a series of advanced metastatic cases.ResultsThis study demonstrated that in about 20% of cases a different RET mutation profile can be found when comparing primary tumor and its corresponding metastases. Furthermore in 8% of tumors, RET intratumor heterogeneity was observed We also showed that in some cases an imbalance of RET copy number was present. We confirmed a high prevalence (90%) of RET somatic mutations in advanced tumors.Materials and MethodsFifty-six MTC patients (50 somatic and 6 hereditary cases) have been included in the study and a total of 209 specimens have been analysed by direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) has been used to investigate amplification/deletion of RET alleles.ConclusionsIn conclusion, this study showed a genetic intra- and intertumor heterogeneity in MTC, But in only 20% of CASES These results could justify the relatively moderate level of aggressiveness of the disease with respect to more aggressive human tumors that are characterized by a high rate of mutation and heterogeneity.

Background: Medullary thyroid cancer (MTC) is capable of secreting several proteins, such as calcitonin (Ct), carcinoembryonic antigen (CEA), chromogranin and others. Recently, we observed an aggressive MTC with high levels of serum carbohydrate antigen 19.9 (Ca 19.9) and a rapid evolution to death.

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