title: Role of cdk4, p16INK4, and Rb expression in the prognosis of bronchioloalveolar carcinomas.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Molecular Pathology, Institute of Gerontology, Nippon Medical School, Nakahara-ku, Kawasaki, Japan. ciem@nms.ac.jp
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ghazizadeh
authors.forename: Enjing
authors.initials: E
authors.lastname: Jin
authors.forename: Hajime
authors.initials: H
authors.lastname: Shimizu
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Satoru
authors.initials: S
authors.lastname: Arai
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Ohaki
authors.forename: Tamiko
authors.initials: T
authors.lastname: Takemura
authors.forename: Oichi
authors.initials: O
authors.lastname: Kawanami
mesh_terms: D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000276:immunology; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000276:immunology; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases