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Expression of G1-S modulators (p53, p16, p27, cyclin D1, Rb) and Smad4/Dpc4 in intrahepatic cholangiocarcinoma

Yun Kyung Kang1, Woo Ho Kim, Ja June Jang

  • 1Department of Pathology, Inje University Seoul Paik Hospital and Seoul National University College of Medicine, Korea.

Human Pathology
|October 16, 2002
PubMed

Insights

Aberrations in the G1-S cell cycle arrest and TGF-beta/Smad pathways are key to human cancer development. These alterations are frequent in intrahepatic cholangiocarcinomas and correlate with advanced disease stages.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gastroenterology

Background:

  • Aberrations in cell cycle regulation (G1-S arrest) and the TGF-beta/Smad pathway are implicated in human carcinogenesis.
  • Intrahepatic cholangiocarcinoma (ICC) is a complex malignancy where these pathways may play a significant role.

Purpose of the Study:

  • To investigate the alterations in G1-S cell cycle arrest and TGF-beta/Smad pathways in intrahepatic cholangiocarcinomas (ICCs).
  • To correlate these molecular changes with clinicopathological features and disease progression.

Main Methods:

  • Immunohistochemical staining was performed on 42 ICC tissue samples to assess the expression of p53, p16, p27, cyclin D1, Rb, and Smad4.
  • Analysis included evaluation of adjacent biliary dysplasia for similar molecular alterations.

Main Results:

  • High frequencies of abnormalities were observed: p53 (35.7%), cyclin D1 (61.9%), p16 loss (35.7%), p27 loss (31.0%), Rb loss (11.9%), and Smad4 loss (45.2%).
  • Ninety-five percent of ICCs exhibited alterations in at least one pathway, with 50% showing G1-S pathway abnormalities only, 40.5% in both, and 4.8% in TGF-beta/Smad only.
  • Loss of Smad4 correlated with advanced pTNM stage (P < 0.05).
  • A higher number of gene alterations (2-5) was associated with significantly higher tumor stage (P < 0.01).
  • Abnormal expression of p53, cyclin D1, or p16 was found in 7 of 13 dysplastic lesions.

Conclusions:

  • Altered G1-S cell cycle regulation and TGF-beta/Smad signaling are critical events in cholangiocarcinogenesis.
  • A cumulative effect of these molecular alterations may influence the clinical outcome in patients with resectable ICCs.

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