Endocrine Abstracts (2016) 40 P1 | DOI: 10.1530/endoabs.40.P1

Genetic heterogeneity of medullary thyroid carcinoma

Cristina Romei, Raffaele Ciampi, Alessia Tacito, Francesca Casella, Clara Ugolini, Mireira Porta, Liborio Torregrossa, Fulvio Basolo & Rossella Elisei


Departement of Clinical and Experimental Medicine, Department of Surgical Pathology, University of Pisa, Pisa, Italy.


Genetic intratumor heterogeneity has been recently demonstrated in some solid human cancers and a few years ago RET mutated and not mutated cells were described in medullary thyroid carcinoma (MTC). Nobody reported the presence of two different RET mutations.

Aim of our study was to investigate the RET somatic mutation profile in primary MTC (pMTC) and in the corresponding metastatic tissues (mets).

We studied pMTC and mets of 22 MTC sporadic cases. Altogether 86 samples were screened for the presence of a RET somatic mutations in exons 10, 11, 13-16.

In 18 cases (81.8%), 57 different tissues, a correspondent mutation profile was found in the pMTC and in their mets. In 4 cases (18.2%), 29 different tissues, a different RET mutation profile was observed in pMTC and in their mets. In particular in one case a M918T was found in the pMTC but only in 3/5 lymphnode mets; in another case, a 3 bp in frame deletion in exon 15 was found in 8 lymphnode mets but not in the primary tumor and in 4 additional lymphnode mets. Interestingly we found one patient with a S891A somatic mutation in the primary tumor that was absent in a kidney distant metastases that was indeed characterized by the presence of a M918T mutation. A complex genetic heterogeneity was finally demonstrated in one MTC patient with a very severe disease. The primary tumor displayed a heterozygous 6 bp in frame deletion in exon 11 that was found also in 4/5 lymphnode metastases and in 1/2 liver metastatisis. In 1/5 lymphnode and in 1/2 liver metastasis the deletion was homozygous. The analysis of several RET SNPs demonstrated that in this case 1 RET allele was missing. In addition both the primary tissue and 4 lymph node metastases harbored a V804M mutation.

In conclusion our study shows that i) 81% of cases had a correspondent RET mutation profile, although in these cases we cannot exclude the simultaneous presence of RET positive and RET negative cells; ii) 19% of cases are clearly heterogeneous and among them 2/4 have different RET mutations in different tissues. This information should be taken into consideration in the planning of personalized target therapies and raise the question of whether RET mutations play a real driving role in the development of MTC.

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