PTEN
PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a lipid/protein phosphatase that plays a role in multiple cell processes, including growth, proliferation, survival, and maintenance of genomic integrity. PTEN acts as a tumor suppressor by negatively regulating the PI3K/AKT signaling pathway (Figure 1) via dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) at the cell membrane.
Cancer-associated alterations in PTEN often result in PTEN inactivation and thus increased activity of the PI3K-AKT pathway. Somatic mutations of PTEN occur in multiple malignancies, including gliomas, melanoma, prostate, endometrial, breast, ovarian, renal, and lung cancers. Germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome (for reviews see Chalhoub and Baker 2009 and Maehama 2007). PTEN activity can also be lost through other mechanisms such as epigenetic changes or post-translational modifications (Leslie and Foti 2010). Immunochemistry is often used to detect changes in expression of PTEN in tumor tissues; low expression is thought to indicate loss of PTEN expression, which would result in increased activity of the PI3K-AKT pathway.
Figure 1. Schematic of the MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.
Related Pathways
Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. PTEN. My Cancer Genome https://www.mycancergenome.org/content/disease/ovarian-cancer/pten/?tab=0 (Updated December 7).
Last Updated: December 7, 2015
PTEN in Ovarian Cancer
Somatic mutations in PTEN have been found in a substantial fraction of Type I ovarian cancers. Frequencies of PTEN mutations in subtypes of ovarian cancer are shown in table 1, and frequencies of specific PTEN mutations in ovarian cancer are shown in table 2. PTEN loss is more common in type I ovarian tumors, but is found in high grade serous, clear cell and endometrioid tumors (Kuo et al. 2009; Geyer et al. 2009; Roh et al. 2010).
Table 1. Frequency of Somatic Gene Mutations in Epithelial Ovarian Cancer (EOC).
Table 2. Frequencies of Specific Mutations.
Contributors: Dineo Khabele, M.D.
Suggested Citation: Khabele, D. 2015. PTEN in Ovarian Cancer. My Cancer Genome https://www.mycancergenome.org/content/disease/ovarian-cancer/pten/ (Updated June 17).
Last Updated: June 17, 2015
PTEN c.389delG (R130fs*4) Mutation in Ovarian Cancer
| Properties |
|---|
| Location of mutation
|
Phosphatase domain (exon 5) |
| Frequency of PTEN mutation
|
1.5% of PTEN-mutated ovarian cancers (COSMIC) |
| Implications for Targeted Therapeutics |
|---|
| Response to PI3K inhibitors |
Unknown at this time |
| Response to AKT inhibitors |
Unknown at this time |
| Response to mTOR inhibitors |
Unknown at this time |
| Response to PI3K/mTOR inhibitors |
Unknown at this time |
| Response to HER2 inhibitors (lapatinib) |
Unknown at this time |
| Response to anti-HER2 antibodies (trastuzumab) |
Unknown at this time |
The R130fs*4 mutation results in a frameshift in the PTEN gene. This mutation occurs within exon 5, which encodes a portion of the phosphatase domain (Chalhoub and Baker 2009).
In vitro studies have shown that inactivating mutations in the PTEN gene confer sensitivity to PI3K-AKT inhibitors [for review, see (Courtney, Corcoran, and Engelman 2010)] as well as FRAP/mTOR inhibitors (Neshat et al. 2001). These findings have yet to be confirmed in clinical trials.
Figure 1. Schematic of R130fs*4 mutation. Functional domains of PTEN are depicted.
Contributors: Dineo Khabele, M.D.
Suggested Citation: Khabele, D. 2014. PTEN c.389delG (R130fs*4) Mutation in Ovarian Cancer. My Cancer Genome https://www.mycancergenome.org/content/disease/ovarian-cancer/pten/143/ (Updated August 8).
Last Updated: August 8, 2014
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