Context: Genetic aberration in PI3K/AKT pathway have been detected in numerous and diverse human cancers. PIK3CA, which encodes for the catalytic subunit of p110 of PI3-kinase, is amplified in some cases of papillary thyroid cancer (PTC). Mutations in the PIK3CA have also been identified in thyroid cancers and though relatively common in anaplastic thyroid carcinoma (ATC), are uncommon in PTC.

Objective: To investigate genetic alterations like PIK3CA gene mutation, PIK3CA amplification, RAS and RAF mutations. To further explore the relationship of these genetic alterations with various clinicopathological characteristics in Middle Eastern PTC.

Design: We used FISH technique for analysis of PIK3CA amplification from 536 PTC cases and selected amplified samples were further validated by real-time quantitative PCR. Mutation analysis was done by direct DNA sequencing of PIK3CA, N2-RAS, BRAF genes.

Results: PIK3CA amplification was seen in 265 of 499 (53.1%) PTC cases analyzed; PIK3CA gene mutations in 4/207 PTC (1.9%); N2-RAS mutations in 16/265 PTC (6%) and BRAF mutations in 153/296 PTC (51.7%). N-RAS mutations were associated with an early stage (P = 0.0465) and lower incidence of extrthyroidal extension (P = 0.027), while BRAF mutations were associated with metastasis (P = 0.0274) and poor disease free survival (P = 0.0121) in PTCs.

Conclusion: A higher incidence of PIK3CA alterations and the possible synergistic effect of PIK3CA alterations and BRAF mutations suggest their major role in Middle Eastern PTC tumorgenesis and argue for therapeutic targeting of PI3K/AKT and MAP kinase pathways.