Role of cdk4, p16<sup>INK4</sup>, and Rb Expression in the Prognosis of Bronchioloalveolar Carcinomas

Vol. 72, No. 1, 2005

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Clinical Investigations

Role of cdk4, p16^INK4, and Rb Expression in the Prognosis of Bronchioloalveolar Carcinomas
Mohammad Ghazizadeh^a, Enjing Jin^a, Hajime Shimizu^a, Masakazu Fujiwara^a, Satoru Arai^b, Yoshiharu Ohaki^b, Tamiko Takemura^c, Oichi Kawanami^a

^aDepartment of Molecular Pathology, Institute of Gerontology, Nippon Medical School, Nakahara-ku, Kawasaki,
^bDivision of Surgical Pathology, Chiba Hokusoh Hospital, Nippon Medical School, Chiba, and
^cSurgical Pathology Section, Nippon Red Cross Hospital Center, Tokyo, Japan

Address of Corresponding Author

Respiration 2005;72:68-73 (DOI: 10.1159/000083403)

Key Words

p16^INK4
Cyclin-dependent kinase 4
Retinoblastoma protein
Bronchioloalveolar carcinoma

Abstract

Background: The p16^INK4 protein has been identified as a potent inhibitor of cyclin-dependent kinase (cdk)4 by blocking cdk4-mediated phosphorylation of the tumor suppressor retinoblastoma (Rb) protein, thus allowing Rb-mediated growth suppression. Objectives: Loss of p16^INK4 has been associated with a poor cancer prognosis, but its potential significance in bronchioloalveolar carcinomas (BACs) has not been explored. Methods: We examined immunohistochemical expression of p16^INK4, cdk4, and Rb proteins in 38 BACs and correlated their expression levels with known clinicopathological features of the disease. Results: All BACs expressed cdk4, while 89 and 82% expressed p16^INK4 and Rb proteins, respectively. None of the clinicopathological factors correlated with p16^INK4, cdk4, or Rb expression separately. A low p16^INK4/cdk4 ratio was significantly associated with a high disease stage (p = 0.04), and the ratio tended to be lower in mucinous than nonmucinous tumors. BACs with a low p16^INK4/cdk4 ratio showed significantly higher Rb expression levels (p = 0.02). Univariable survival analyses showed a significantly lower 5-year survival probability in patients with a high stage (p = 0.002) or low p16^INK4/cdk4 ratio (p = 0.01). Conclusions: The results suggest a role of the cdk4/p16^INK4 pathway in the prognosis of BACs. Further studies are warranted to clarify whether a low p16^INK4/cdk4 ratio may identify tumors that are destined to behave unfavorably.

Author Contacts

M. Ghazizadeh, MD, PhD
Department of Molecular Pathology, Institute of Gerontology
Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku
Kawasaki 211-8533 (Japan)
Tel. +81 44 733 1821, Fax +81 44 733 1293, E-Mail ciem@nms.ac.jp

Article Information

Received: January 25, 2004
Accepted after revision: June 25, 2004
Number of Print Pages : 6
Number of Figures : 3, Number of Tables : 1, Number of References : 26

Medline Abstract (ID 15753637)

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