Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population.
BACKGROUND
Genetic aberration in phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been detected in numerous and diverse human cancers. PIK3CA, which encodes for the catalytic subunit of p110alpha of PI3K, is amplified in some cases of papillary thyroid cancer (PTC). Mutations in the PIK3CA have also been identified in thyroid cancers and, although relatively common in anaplastic thyroid carcinoma, are uncommon in PTC.


OBJECTIVE
The objective of the study was to investigate genetic alterations like PIK3CA gene mutation, PIK3CA amplification, RAS, and RAF mutations and to further explore the relationship of these genetic alterations with various clinicopathological characteristics in Middle Eastern PTC.


METHODS
We used the fluorescence in situ hybridization 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, and BRAF genes.


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


CONCLUSIONS
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 tumorigenesis and argue for therapeutic targeting of PI3K/AKT and MAPK pathways.
Abubaker
Jehad
J
Department of Human Cancer Genomic Research, King Fahad National Center for Children's Cancer and Research, King Faisal Specialist Hospital and Research Cancer, MBC#98-16, P.O. Box 3354, Riyadh 11211, Saudi Arabia.
Jehan
Zeenath
Z
Bavi
Prashant
P
Sultana
Mehar
M
Al-Harbi
Sayer
S
Ibrahim
Muna
M
Al-Nuaim
Abdulrahman
A
Ahmed
Mohammed
M
Amin
Tarek
T
Al-Fehaily
Maha
M
Al-Sanea
Osama
O
Al-Dayel
Fouad
F
Uddin
Shahab
S
Al-Kuraya
Khawla S
KS
D000328:Adult; D002291:Carcinoma, Papillary / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D008877:Middle East; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D017422:Sequence Analysis, DNA; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D018631:ras Proteins / Q000235:genetics
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; D018631:ras Proteins