Endocrine Abstracts

Introduction: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that originates from the parafollicular thyroid cells (C cells); MTC occurs as both a hereditary disease (25% of all cases), when MTC in a manifestation of multiple endocrine neoplasia type 2 or 3 (MEN 2/3) and as sporadic disease. The hereditary type is a consequence of germline mutation in the rearranged during transfection (RET) proto-oncogene, which can undergo oncogenic activation through both cytogenetic rearrangement and activation of point mutation. Other types of mutations are acquired (or somatic), found in up to 55% of patients with sporadic MTC and are associated with disease aggressiveness. Patient’s genotype influences the clinical management for themselves as well for their families. Thyrosine kinase inhibitors (TKIs) were approved for advanced MTC cases with RET alterations.

Patients and methods: We performed genetic testing for germline RET mutations on 82 subjects (58 complete gene analyses and 24 targeted analyses). Genomic DNA was extracted from peripheral blood, and mutational screening was performed according to a standard algorithm approved by the American and European MTC management Guidelines. In addition, genomic DNA was extracted from tissue samples using fresh or formalin-fixed, paraffin-embedded tumor for somatic RET mutation. In patients with detected germline RET mutation, somatic status was assumed to be identical, and the test was not repeated on tumour DNA.

Results: A germline RET variant was identified in a total of 31/82 (37.8%) patients. From them, all cases with positive family history 24/24 (100%) and 7/58 (12.06%) cases initially considered sporadic were diagnosed as hereditary MTC. Five different RET variants, were identified in our sample. The most common RET proto-oncogene alteration was found in exon 11, codon 634 in 14/31 (45.16%) cases. From a total of 8 patients tested for somatic RET mutations, 6/8 (75%) were found positive. Among those, the most common mutation, 5/6 cases, was M918T mutation, and in one case C634A mutation. We observed a more aggressive disease (metastatic, progressive) in all patients with somatic RET mutation, requiring treatment with TKIs, vandetanib or cabozantinib.

Conclusion: Mutational screening is mandatory in all patients with MTC, allowing the detection of germline mutations in initially “so-called” sporadic MTC, which could trigger family genetic screening. Precision genetic-based oncology with targeted treatment, such as TKIs, could improve survival in advanced medullary thyroid cancers.