High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma.
The phosphatidylinositol 3'-kinase (PI3K) pathway is activated in many human cancers. In addition to inactivation of the PTEN tumor suppressor gene, mutations or amplifications of the catalytic subunit alpha of PI3K (PIK3CA) have been reported. However, the coexistence of mutations in these two genes seems exceedingly rare. As PTEN mutations occur at high frequency in endometrial carcinoma, we screened 66 primary endometrial carcinomas for mutations in the helical and catalytic domains of PIK3CA. We identified a total of 24 (36%) mutations in this gene and coexistence of PIK3CA/PTEN mutations at high frequency (26%). PIK3CA mutations were more common in tumors with PTEN mutations (17 of 37, 46%) compared with those without PTEN mutations (7 of 29, 24%). Array comparative genomic hybridization detected 3q24-qter amplification, which covers the PIK3CA gene (3q26.3), in one of nine tumors. Knocking down PTEN expression in the HEC-1B cell line, which possesses both K-Ras and PIK3CA mutations, further enhances phosphorylation of Akt (Ser473), indicating that double mutation of PIK3CA and PTEN has an additive effect on PI3K activation. Our data suggest that the PI3K pathway is extensively activated in endometrial carcinomas, and that combination of PIK3CA/PTEN alterations might play an important role in development of these tumors.
Oda
Katsutoshi
K
Cancer Research Institute, University of California San Francisco, San Francisco, California 94115, USA.
Stokoe
David
D
Taketani
Yuji
Y
McCormick
Frank
F
D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human