• What is PTEN?
  • PTEN in Ovarian Cancer
  • PTEN c.968dupA (N323fs*2)
  • Clinical Trials


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.padiracinnovation.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).

  EOC Overall Type I Type II
Gene Mutation   Low Grade Serous Clear Cell Endometrioid Mucinous High Grade Serous
PTEN 20% (Kurman and Shih 2011) <1% mutation (TCGA 2011) 20% (Landen, Birrer, and Sood 2008) <1–5% (Kuo et al. 2009; Willner et al. 2007​) 20–31% (Kurman and Shih 2011; Willner et al. 2007) Rare

Table 2. Frequencies of Specific Mutations.

Gene Amino Acid Position Amino Acid Change Nucleotide Change Frequency Among PTEN-Mutated Ovarian Cancer (COSMIC)
PTEN R130 p.R130G c.388C>G 6.2%
p.R130* c.388C>T 7.7%
p.R130Q c.389G>A 1.5%
p.R130fs*4 c.389delG 1.5%
P248 p.P248fs*5 c.741dupA 3.1%
N323 p.N323fs*2 c.968supA 1.5%
p.N323fs*21 c.968delA​ 3.1%


Contributors: Dineo Khabele, M.D.

Suggested Citation: Khabele, D. 2015. PTEN in Ovarian Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/ovarian-cancer/pten/ (Updated June 17).

Last Updated: June 17, 2015

PTEN c.968dupA (N323fs*2) Mutation in Ovarian Cancer

Location of mutation C2 domain (exon 8)
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 N323fs*2 mutation results in a frameshift in the PTEN gene. This mutation occurs within exon 8, which encodes a portion of the C2 domain (Chalhoub and Baker 2009). C2 domains are known to be involved in targeting proteins to cell membranes.

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 N323fs*2 mutation. Functional domains of PTEN are depicted.

Contributors: Dineo Khabele, M.D.

Suggested Citation: Khabele, D. 2014. PTEN c.968dupA (N323fs*2) Mutation in Ovarian Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/ovarian-cancer/pten/140/ (Updated August 8).

Last Updated: August 8, 2014

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