Journal of Clinical Oncology, Vol 21, Issue 17
(September), 2003: 3226-3235
© 2003 American Society for Clinical Oncology
ras Mutations Are Associated With Aggressive Tumor Phenotypes and Poor Prognosis in Thyroid Cancer
Ginesa Garcia-Rostan,
Hongyu Zhao,
Robert L. Camp,
Marina Pollan,
Agustin Herrero,
Javier Pardo,
Ran Wu,
Maria Luisa Carcangiu,
Jose Costa,
Giovanni Tallini
From the Departments of Pathology, Epidemiology and Public Health, and Psychiatry, Yale University School of Medicine, New Haven, CT; Cancer Epidemiology Service, National Center for Epidemiology, National Institute of Health Carlos III, Madrid; Department of Pathology, Oviedo University School of Medicine, Oviedo; and Department of Pathology, Navarra University School of Medicine, Pamplona, Spain.
Address reprint requests to Giovanni Tallini, MD, Anatomia Patologica, Università di Bologna-Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy; e-mail: Giovanni.Tallini{at}ausl.bologna.it. or Ginesa Garcia-Rostan, MD, Instituto de Patologia e Immunologia Molecular de Universidade do Porto, Rua Roberto Frias, 4200 Porto, Portugal; e-mail: grostan{at}ipatimup.pt.
Purpose: ras oncogenic activation has long been demonstrated in thyroid carcinomas of follicular cell derivation, but no consistent relationship has been shown between mutations and clinicopathologic features.
Materials and Methods: We analyzed H-, K-, and N-ras mutations by polymerase chain reaction–single-strand conformational polymorphism followed by DNA sequencing in 125 thyroid carcinoma specimens from 107 patients, to include tumors covering the entire spectrum of thyroid tumor differentiation.
Results: Mutations were identified in four (8.2%) of 49 well-differentiated carcinomas (WDCs; two [6.7%] of 30 of the tumors were papillary carcinomas, two [10.5%] of 19 of them were follicular carcinomas), in 16 (55.2%) of 29 poorly differentiated carcinomas (PDCs), and in 15 (51.7%) of 29 undifferentiated carcinomas, with a significant association between ras mutation and poorly or undifferentiated tumors (P < .001). Twenty-six (74.3%) of 35 patients with ras-mutated tumors died as a result of disease as opposed to 23 (31.9%) of 72 patients with tumors lacking the mutations. Among patients with differentiated thyroid carcinomas (WDC and PDC), 11 (55.0%) of 20 patients with mutated tumors died as a result of disease as opposed to nine (15.5%) of 58 patients with wild-type ras tumors, and the correlation was independent of tumor differentiation and stage (P = .016). K-ras codon 13 mutations (all with G-A nucleotide transitions resulting in Gly>Asp substitution) and single activating mutations in any of the ras genes were also independent predictors of poor survival in differentiated thyroid carcinomas (P = .027 and P = .007, respectively).
Conclusion: These findings demonstrate that ras mutations are a marker for aggressive cancer behavior and indicate a possible role of ras genotyping to identify thyroid carcinoma subsets associated with poor prognosis.
Supported in part by FIS grants (files 97/5063 and 98/5022) from the Spanish Government to G.G.R. and by a grant from the Thyroid Research Advisory Council of Knoll Pharmaceutical Company (grant SYN 0400 08) to G.T.
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