PURPOSE: The goal of this study was to comprehensively define the incidence of 
mutations in all exons of PIK3CA in both endometrioid endometrial cancer (EEC) 
and nonendometrioid endometrial cancer (NEEC).
EXPERIMENTAL DESIGN: We resequenced all coding exons of PIK3CA and PTEN, and 
exons 1 and 2 of KRAS, from 108 primary endometrial tumors. Somatic mutations 
were confirmed by sequencing matched normal DNAs. The biochemical properties of 
a subset of novel PIK3CA mutations were determined by exogenously expressing 
wild type and mutant constructs in U2OS cells and measuring levels of 
AKT(Ser473) phosphorylation.
RESULTS: Somatic PIK3CA mutations were detected in 52.4% of 42 EECs and 33.3% of 
66 NEECs. Half (29 of 58) of all nonsynonymous PIK3CA mutations were in exons 
1-7 and half were in exons 9 and 20. The exons 1-7 mutations localized to the 
ABD, ABD-RBD linker and C2 domains of p110α. Within these regions, Arg88, Arg93, 
Gly106, Lys111, Glu365, and Glu453, were recurrently mutated; Arg88, Arg93, and 
Lys111 formed mutation hotspots. The p110α-R93W, -G106R, -G106V, -K111E, 
-delP449-L455, and -E453K mutants led to increased levels of phospho-AKT(Ser473) 
compared to wild-type p110α. Overall, 62% of exons 1-7 PIK3CA mutants and 64% of 
exons 9-20 PIK3CA mutants were activating; 72% of exon 1-7 mutations have not 
previously been reported in endometrial cancer.
CONCLUSIONS: Our study identified a new subgroup of endometrial cancer patients 
with activating mutations in the amino-terminal domains of p110α; these patients 
might be appropriate for consideration in clinical trials of targeted therapies 
directed against the PI3K pathway.