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Molecular alterations associated with cyclin D1 overexpression in endometrial cancer

Gema Moreno-Bueno1, Sandra Rodríguez-Perales, Carolina Sánchez-Estévez

  • 1Laboratory of Breast and Gynecologic Cancer, Molecular Pathology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.

International Journal of Cancer
|April 8, 2004
PubMed

Insights

Cyclin D1 overexpression in endometrial cancer (EC) differs by type. In normal endometrial hyperplasias (AEHs), it was absent. Endometrial intraepithelial neoplasia (EIN) showed CCND1 amplification, while endometrioid EC (EEC) linked it to beta-catenin and microsatellite instability.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cyclin D1 overexpression is common in human cancers, often due to gene amplification.
  • The mechanisms driving cyclin D1 overexpression in endometrial cancer (EC) are not fully understood.
  • Ras, PTEN, and beta-catenin are known modulators of cyclin D1 levels.

Purpose of the Study:

  • To investigate the causes of cyclin D1 overexpression in EC, specifically gene amplification versus mutations in RAS, PTEN, and beta-catenin.
  • To analyze cyclin D1 expression and CCND1 gene amplification in different endometrial pathologies.
  • To explore the relationship between cyclin D1 alterations and molecular markers like mutations and microsatellite instability (MSI).

Main Methods:

  • Immunohistochemistry for cyclin D1 expression.
  • Fluorescence in situ hybridization (FISH) for CCND1 gene amplification.
  • Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing for mutations in K-RAS, PTEN, and beta-catenin.
  • Microsatellite analysis (BAT-25, BAT-26) for MSI evaluation.

Main Results:

  • Cyclin D1 overexpression was observed in endometrioid EC (13.8%) and non-endometrioid EC (11.2%), but not in atypical hyperplasia (AEH).
  • CCND1 amplification was significantly more frequent in non-endometrioid EC (26.3%) compared to endometrioid EC (2.1%).
  • In endometrioid EC, cyclin D1 overexpression was not linked to K-RAS, PTEN, or beta-catenin mutations but was associated with nucleocytoplasmic beta-catenin expression and MSI.

Conclusions:

  • The molecular drivers of cyclin D1 overexpression vary between endometrioid EC and non-endometrioid EC.
  • In non-endometrioid EC, cyclin D1 overexpression is associated with CCND1 gene amplification.
  • In endometrioid EC, cyclin D1 overexpression is linked to specific beta-catenin localization and microsatellite instability.

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