title: High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability.
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.
authors: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054-1942. wcheung@mdanderson.org
authors: Lydia W T
authors: LW
authors: Cheung
authors: Bryan T
authors: BT
authors: Hennessy
authors: Jie
authors: J
authors: Li
authors: Shuangxing
authors: S
authors: Yu
authors: Andrea P
authors: AP
authors: Myers
authors: Bojana
authors: B
authors: Djordjevic
authors: Yiling
authors: Y
authors: Lu
authors: Katherine
authors: K
authors: Stemke-Hale
authors: Mary D
authors: MD
authors: Dyer
authors: Fan
authors: F
authors: Zhang
authors: Zhenlin
authors: Z
authors: Ju
authors: Lewis C
authors: LC
authors: Cantley
authors: Steven E
authors: SE
authors: Scherer
authors: Han
authors: H
authors: Liang
authors: Karen H
authors: KH
authors: Lu
authors: Russell R
authors: RR
authors: Broaddus
authors: Gordon B
authors: GB
authors: Mills
mesh_terms: D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics* / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D020930:MAP Kinase Kinase Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C117307:KRAS protein, human; C560566:phosphoinositol-3 kinase regulatory subunit 2, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C494929:PTEN protein, human