Context: Anaplastic thyroid carcinoma (ATC) can arise 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 (PI3K)/Akt signaling pathways play critical roles in DTC tumorigenesis, but their roles in the pathogenesis of ATC are poorly defined.

Objective: To explore the potential contributions of these 2 pathways in ATC pathogenesis.

Design, setting and subjects: 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 (LN). 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 9 of 36 ATCs (25%); 7 cases had identical mutations in both the ATC and DTC components. PIK3CA kinase domain mutations were found in 5 ATC (14%), 1 of which had mutations in both differentiated and anaplastic areas. RAS and PTEN mutations were each found in 2 ATC (6%). PIK3CA gain copy number was found notably increased in 14 ATC (39%).

Conclusions: BRAF mutations appear to play a role in the tumorigenesis of a subset of ATC, and the majority of LN. 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.