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Prognostic Significance of Somatic RET Oncogene Mutations in Sporadic Medullary Thyroid Cancer: A 10-Year Follow-Up Study

Departments of Endocrinology and Metabolism (R.E., B.C., C.R., V.B., G.R., E.M., L.A., A.V., A.P.), of Oncology (P.F., F.B.), and of Surgery (P.M., P.B.), University of Pisa 56100 Pisa, Italy; Department of Internal Medicine, Endocrinology and Metabolism, and Biochemistry (F.P.), University of Siena, 53100 Siena, Italy; and AMBISEN Center (A.P.), High Technology Center for the Study of the Environmental Damage of the Endocrine and Nervous Systems, University of Pisa, 56124 Pisa, Italy

Address all correspondence and requests for reprints to: R. Elisei, M.D., Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. E-mail: relisei{at}endoc.med.unipi.it.

Background: Medullary thyroid carcinoma (MTC) is a well-differentiated thyroid tumor that maintains the typical features of C cells. An advanced stage and the presence of lymph node metastases at diagnosis have been demonstrated to be the most important bad prognostic factors. Somatic RET mutations have been found in 40–50% of MTCs. Although a relationship between somatic mutations and bad prognosis has been described, data are controversial and have been performed in small series with short-term follow ups. The aim of this study was to verify the prognostic value of somatic RET mutations in a large series of MTCs with a long follow up.

Methods: We studied 100 sporadic MTC patients with a 10.2 yr mean follow-up. RET gene exons 10–11 and 13–16 were analyzed. The correlation between the presence/absence of a somatic RET mutation, clinical/pathological features, and outcome of MTC patients was evaluated.

Results: A somatic RET mutation was found in 43 of 100 (43%) sporadic MTCs. The most frequent mutation (34 of 43, 79%) was M918T. RET mutation occurrence was more frequent in larger tumors (P = 0.03), and in MTC with node and distant metastases (P < 0.0001 and P = 0.02, respectively), thus, a significant correlation was found with a more advanced stage at diagnosis (P = 0.004). A worse outcome was also significantly correlated with the presence of a somatic RET mutation (P = 0.002). Among all prognostic factors found to be correlated with a worse outcome, at multivariate analysis only the advanced stage at diagnosis and the presence of a RET mutation showed an independent correlation (P < 0.0001 and P = 0.01, respectively). Finally, the survival curves of MTC patients showed a significantly lower percentage of surviving patients in the group with RET mutations (P = 0.006).

Conclusions: We demonstrated that the presence of a somatic RET mutation correlates with a worse outcome of MTC patients, not only for the highest probability to have persistence of the disease, but also for a lower survival rate in a long-term follow up. More interestingly, the presence of a somatic RET mutation correlates with the presence of lymph node metastases at diagnosis, which is a known bad prognostic factor for the definitive cure of MTC patients.

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