title: Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study.
abstract: 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.
authors: Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. relisei@endoc.med.unipi.it
authors: Rossella
authors: R
authors: Elisei
authors: Barbara
authors: B
authors: Cosci
authors: Cristina
authors: C
authors: Romei
authors: Valeria
authors: V
authors: Bottici
authors: Giulia
authors: G
authors: Renzini
authors: Eleonora
authors: E
authors: Molinaro
authors: Laura
authors: L
authors: Agate
authors: Agnese
authors: A
authors: Vivaldi
authors: Pinuccia
authors: P
authors: Faviana
authors: Fulvio
authors: F
authors: Basolo
authors: Paolo
authors: P
authors: Miccoli
authors: Piero
authors: P
authors: Berti
authors: Furio
authors: F
authors: Pacini
authors: Aldo
authors: A
authors: Pinchera
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality; D013997:Time Factors
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human