Abstract
We demonstrate that phosphatidylinositol 3-kinase (PI3K) pathway aberrations occur in >80% of endometrioid endometrial cancers, with coordinate mutations of multiple PI3K pathway members being more common than predicted by chance. PIK3R1 (p85α) mutations occur at a higher rate in endometrial cancer than in any other tumor lineage, and PIK3R2 (p85β), not previously demonstrated to be a cancer gene, is also frequently mutated. The dominant activation event in the PI3K pathway appears to be PTEN protein loss. However, in tumors with retained PTEN protein, PI3K pathway mutations phenocopy PTEN loss, resulting in pathway activation. KRAS mutations are common in endometrioid tumors activating independent events from PI3K pathway aberrations. Multiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85α dimers bind and stabilize PTEN. Taken together, the PI3K pathway represents a critical driver of endometrial cancer pathogenesis and a novel therapeutic target.
Keywords:
Endometrial Cancer; PIK3CA; PIK3R1; PIK3R2; PTEN.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Transformed
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Cell Line, Tumor
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Class I Phosphatidylinositol 3-Kinases
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Class Ia Phosphatidylinositol 3-Kinase / genetics*
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Class Ia Phosphatidylinositol 3-Kinase / metabolism
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Endometrial Neoplasms / genetics*
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Endometrial Neoplasms / metabolism
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Female
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HEK293 Cells
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Humans
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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Mutation
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PTEN Phosphohydrolase / genetics*
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PTEN Phosphohydrolase / metabolism*
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Phosphatidylinositol 3-Kinases / genetics*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins p21(ras)
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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ras Proteins / genetics
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ras Proteins / metabolism
Substances
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KRAS protein, human
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Proto-Oncogene Proteins
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phosphoinositol-3 kinase regulatory subunit 2, human
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MTOR protein, human
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Class I Phosphatidylinositol 3-Kinases
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Class Ia Phosphatidylinositol 3-Kinase
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PIK3CA protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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MAP Kinase Kinase Kinases
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PTEN Phosphohydrolase
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PTEN protein, human
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Proto-Oncogene Proteins p21(ras)
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ras Proteins