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Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian

Carmela De Marco1, Nicola Rinaldo, Paola Bruni

  • 1Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy.

Plos One
|February 15, 2013
PubMed

Insights

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is hyperactive in ovarian cancer, particularly in older patients. PI3K p110α overexpression is the most common alteration, but often requires additional genetic changes for AKT activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is frequently activated in various cancers, including ovarian carcinoma (OC).
  • The specific contributions of individual PI3K pathway components to AKT activation in OC remain incompletely understood.

Purpose of the Study:

  • To investigate the alterations in the PI3K pathway and their role in AKT activation in Italian OC patient tumor samples.
  • To determine the frequency and type of genetic and protein alterations within the PI3K pathway in OC.

Main Methods:

  • Analysis of 98 OC tumor samples for genetic and protein alterations in PI3K pathway members.
  • Utilized techniques including FISH (Fluorescence In Situ Hybridization) to assess gene amplification and protein expression levels.
  • Compared alterations in OC tissues with normal adjacent tissues.

Main Results:

  • AKT was significantly hyperactive in OC compared to normal tissue (p<0.0001), with preferential activation in older patients (>58 years).
  • The most frequent alteration was PI3K p110α catalytic subunit overexpression (∼68%), followed by PTEN loss (27%), AKT1 overexpression (19%), and AKT2 overexpression (12.5%).
  • PIK3CA gene amplification and PTEN loss were common, correlating with protein expression changes. Multiple pathway alterations were observed in 35/93 OC cases.

Conclusions:

  • p110α overexpression is the most frequent PI3K/AKT pathway alteration in OC.
  • p110α overexpression alone may not be sufficient for AKT signaling activation and ovarian tumorigenesis; additional alterations are often necessary.
  • Aberrant PI3K signaling is mediated by AKT-dependent pathways and affects oncogenic transcription factors.

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