ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Garcia-Rostan
Ginesa
G
Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. grostan@ipatimup.pt.
Zhao
Hongyu
H
Camp
Robert L
RL
Pollan
Marina
M
Herrero
Agustin
A
Pardo
Javier
J
Wu
Ran
R
Carcangiu
Maria Luisa
ML
Costa
Jose
J
Tallini
Giovanni
G
D018265:Carcinoma, Papillary, Follicular / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D011905:Genes, ras; D006801:Humans; D016015:Logistic Models; D008297:Male; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D017421:Sequence Analysis; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology*