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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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