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Genetic alterations in the phosphatidylinositol-3 kinase/Akt pathway in thyroid cancer

Mingzhao Xing1

  • 1Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. mxing1@jhmi.edu

Thyroid : Official Journal of the American Thyroid Association
|June 29, 2010
PubMed
Abstract

Insights

Genetic alterations in the phosphatidylinositol-3 kinase (PI3K)/Akt pathway drive thyroid cancer development and progression. Understanding these changes, including mutations and copy gains, is crucial for developing new diagnostic and therapeutic strategies for thyroid cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Aberrant activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway is fundamental in thyroid tumorigenesis, especially in follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC).
  • Numerous genetic alterations activating the PI3K/Akt pathway have been identified as key drivers in thyroid cancer.
  • These alterations are particularly prevalent in aggressive forms of thyroid cancer.

Purpose of the Study:

  • To review and summarize the major genetic alterations within the PI3K/Akt pathway implicated in thyroid cancer.
  • To elucidate the role of these genetic alterations in thyroid tumorigenesis and cancer progression.
  • To highlight the potential for genetic-based diagnostic and therapeutic strategies.

Main Methods:

  • Review of current literature on genetic alterations in the PI3K/Akt pathway in thyroid cancer.
  • Analysis of the prevalence and types of genetic alterations across different thyroid cancer subtypes (PTC, FTC, ATC).
  • Examination of the interplay between PI3K/Akt and MAPK pathways and their genetic drivers.

Main Results:

  • Key genetic alterations include PIK3CA mutations, Ras mutations, PTEN mutations, and rearrangements like RET/PTC and PPARgamma/Pax8.
  • Amplifications or copy gains of PIK3CB, PDK1, Akt, and receptor tyrosine kinase genes are also significant.
  • These alterations are more common in FTC and ATC than in papillary thyroid cancer (PTC), where the MAPK pathway is dominant.
  • Epigenetic silencing of PTEN via methylation acts synergistically with genetic alterations.
  • Genetic alterations show increasing concurrence from benign to FTC to ATC, with some mutually exclusive in differentiated tumors.
  • RET/PTC, Ras, and receptor tyrosine kinases can activate both PI3K/Akt and MAPK pathways, particularly in ATC.
  • Accumulation of alterations activating both pathways correlates with increased aggressiveness and progression to ATC.

Conclusions:

  • Genetic alterations in the PI3K/Akt pathway are prevalent and play a critical role in thyroid cancer initiation and progression.
  • These findings provide a strong foundation for developing novel genetic-based diagnostic, prognostic, and therapeutic approaches for thyroid cancer.
  • Targeting the PI3K/Akt pathway and understanding its interplay with other signaling pathways offers promising avenues for future cancer treatment.

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