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A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas
Meghan L Rudd1, Jessica C Price, Sarah Fogoros
1Cancer Genetics Branch, National Human Genome Research Institute, National Cancer Institute, Bethesda, Maryland, USA.
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.
Insights
Activating mutations in PIK3CA were common in endometrial cancers, particularly in the amino-terminal domains of p110α. These PIK3CA mutations may identify patients for PI3K pathway targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Endometrial cancer is a common gynecologic malignancy with distinct subtypes.
- PIK3CA gene mutations are implicated in various cancers, but their role in different endometrial cancer types requires comprehensive analysis.
Purpose of the Study:
- To determine the frequency of mutations across all exons of the PIK3CA gene in both endometrioid endometrial cancer (EEC) and nonendometrioid endometrial cancer (NEEC).
- To investigate the functional impact of novel PIK3CA mutations on the PI3K/AKT pathway.
Main Methods:
- Resequencing of all coding exons of PIK3CA and PTEN, and exons 1-2 of KRAS in 108 endometrial tumors.
- Confirmation of somatic mutations using matched normal DNA.
- Biochemical analysis of mutant PIK3CA constructs in U2OS cells to assess AKT phosphorylation.
Main Results:
- PIK3CA mutations were found in 52.4% of EEC and 33.3% of NEEC.
- Mutations were distributed across N-terminal (exons 1-7) and C-terminal (exons 9, 20) domains, with hotspots identified in the N-terminal region.
- Several novel N-terminal PIK3CA mutations demonstrated increased AKT phosphorylation, indicating pathway activation.
Conclusions:
- A distinct subgroup of endometrial cancer patients with activating PIK3CA mutations in N-terminal domains was identified.
- These findings suggest potential eligibility for targeted therapies within clinical trials focused on the PI3K pathway.
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