RGD Reference Report - High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. - Rat Genome Database

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High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability.

Authors: Cheung, Lydia W T  Hennessy, Bryan T  Li, Jie  Yu, Shuangxing  Myers, Andrea P  Djordjevic, Bojana  Lu, Yiling  Stemke-Hale, Katherine  Dyer, Mary D  Zhang, Fan  Ju, Zhenlin  Cantley, Lewis C  Scherer, Steven E  Liang, Han  Lu, Karen H  Broaddus, Russell R  Mills, Gordon B 
Citation: Cheung LW, etal., Cancer Discov. 2011 Jul;1(2):170-85. doi: 10.1158/2159-8290.CD-11-0039. Epub 2011 Jun 7.
RGD ID: 13674179
Pubmed: PMID:21984976   (View Abstract at PubMed)
PMCID: PMC3187555   (View Article at PubMed Central)
DOI: DOI:10.1158/2159-8290.CD-11-0039   (Journal Full-text)

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 (p85ß), 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
endometrial cancer  IAGP 13674179DNA:mutations:multiple (human)RGD 
endometrial cancer  ISOPIK3R1 (Homo sapiens)13674179; 13674179DNA:mutations:multiple (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pik3r1  (phosphoinositide-3-kinase regulatory subunit 1)

Genes (Mus musculus)
Pik3r1  (phosphoinositide-3-kinase regulatory subunit 1)

Genes (Homo sapiens)
PIK3R1  (phosphoinositide-3-kinase regulatory subunit 1)


Additional Information