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Original article
New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with double RET mutations
  1. Cristina Romei1,
  2. Francesca Casella1,
  3. Alessia Tacito1,
  4. Valeria Bottici1,
  5. Laura Valerio1,
  6. David Viola1,
  7. Virginia Cappagli1,
  8. Antonio Matrone1,
  9. Raffaele Ciampi1,
  10. Paolo Piaggi1,
  11. Clara Ugolini2,
  12. Liborio Torregrossa2,
  13. Fulvio Basolo2,
  14. Gabriele Materazzi2,
  15. Paolo Vitti1,
  16. Rossella Elisei1
  1. 1Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
  2. 2Department of Surgical, Medical, Molecular Pathology, University of Pisa, Pisa, Italy
  1. Correspondence to Dr Cristina Romei, Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Pisa, Via Paradisa 2, Pisa IT 56124, Italy; c.romei{at}


Background The RET proto-oncogene is responsible for the pathogenesis of hereditary (98%) and sporadic (40%) medullary thyroid carcinoma (MTC). In sporadic MTC, somatic RET mutations are associated with a poor prognosis.

Objectives We looked at the genetic profile of patients with advanced and metastatic MTC. The correlation between these mutations and outcome was also investigated.

Methods 70 patients with advanced and metastatic sporadic MTC were studied. Exons 10–11 and 13–16 of RET were analysed by direct sequencing. All cases were studied for RAS and the majority also for TERT mutations. RET/RAS-negative cases were analysed for other oncogene mutations.

Results 64/70 cases (91.4%) showed a somatic mutation, while 6 (8.6%) were negative. Among the mutated cases, RET mutations, mainly M918T, were the most prevalent (93.8%). K- or H-RAS mutations were present in 6.2% of cases and were mutually exclusive with RET. No other mutations were found. Four tumours showed two RET somatic mutations. We found a complex somatic RET alteration in 6/60 (10%) RET-positive sporadic MTC cases. A positive correlation between a poor prognosis and the multiple number of RET mutations was found.

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

  • Cancer: endocrine
  • ret
  • medullary thyroid cancer
  • ras

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  • Contributors CR, FC, AT and RC took care of the laboratory investigations. In particular, FC was involved in the collection and processing of tissues. VB, LV, DV, VC, AM, PV and RE are members of the clinical staff of our hospital. In the framework of this study, they have been involved in the selection of patients to be considered for the study and in the collection of clinical information. PP took care of the statistical analysis. CU, LT and FB revised the tissue slide and selected the tissue sections to be processed for DNA analysis. GM is the surgeon entitled to perform total thyroidectomy in patients with MTC. CR and RE prepared the manuscript. All the authors revised the manuscript and contributed to the editing.

  • Funding This work was supported by the Istituto Toscano Tumori (ITT, Grant proposal 2010) and Associazione Italiana Ricerca sul Cancro (AIRC, Investigator grant 2014, project code 15431).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Local ethics committee and Institutional Review Board, University Hospital of Pisa.

  • Provenance and peer review Not commissioned; externally peer reviewed.