Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer.
BACKGROUND
Anaplastic thyroid carcinoma (ATC) can occur in the setting of differentiated thyroid carcinoma (DTC), which suggests a continuum in malignant progression from DTC to ATC. The Ras/Raf-MAPK and the phosphatidylinositol 3-kinase/Akt signaling pathways play critical roles in DTC tumorigenesis, but their roles in the pathogenesis of ATC are poorly defined.


OBJECTIVE
Our objective was to explore the potential contributions of these two pathways in ATC pathogenesis.


METHODS
The mutational status of BRAF, PIK3CA, PTEN, and RAS genes was analyzed in genomic DNA from microdissected tumor specimens of 36 cases of ATC, and in 16 samples of paired-matched lymph node metastases. PIK3CA copy number gain was assessed by real-time quantitative PCR. We performed immunohistochemistry for phospho-ERK and phospho-AKT in 26 cases of ATC.


RESULTS
DTC was present in half of the cases. BRAF V600E mutation was identified in nine of 36 (25%) ATCs; seven cases had identical mutations in both the ATC and DTC components. PIK3CA kinase domain mutations were found in five (14%) ATCs, one of which had mutations in both differentiated and anaplastic areas. RAS and PTEN mutations were each found in two (6%) ATCs. PIK3CA gain copy number was found notably increased in 14 (39%) ATCs.


CONCLUSIONS
BRAF mutations appear to play a role in the tumorigenesis of a subset of ATCs, and the majority of lymph node metastases. PIK3CA alterations occur preferentially in the later stages of ATC and were the most relevant events during thyroid cancer progression. The activation of both pathways suggests an important role in ATC dedifferentiation.
Santarpia
Libero
L
Department of Endocrine Neoplasia and Hormonal Disorders, Unit 435, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, USA.
El-Naggar
Adel K
AK
Cote
Gilbert J
GJ
Myers
Jeffrey N
JN
Sherman
Steven I
SI
D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D004273:DNA, Neoplasm / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000235:genetics*; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism*
D004273:DNA, Neoplasm; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human