title: Abnormal expression of p16(INK4a), cyclin D1, cyclin-dependent kinase 4 and retinoblastoma protein in gastric carcinomas.
abstract: OBJECTIVE
  The p16(INK4a) (p16), cyclin D1, cyclin-dependent kinase (CDK) 4 and retinoblastoma (Rb) genes are components of the Rb pathway that controls the G1-S checkpoint of the cell cycle. The aim of this study was to assess the relationship between their abnormalities and clinicopathological features in gastric carcinomas.
  
  
  METHODS
  Immunohistochemical analysis of the encoded proteins was performed on a series of 158 cases.
  
  
  RESULTS
  Loss of p16/Rb protein (pRb) expression and overexpression of cyclin D1/CDK4 were observed in 49%/40% and 37%/37% of gastric carcinomas, respectively. At least 1 of these abnormalities was found in 86% of the cases and a positive correlation was noted between p16 and pRb (P = 0.009). Cyclin D1 (P = 0.042) and CDK4 (P = 0.008) overexpession was inversely associated with lymph node metastasis and depth of invasion, respectively. Loss of pRb expression was more frequently in diffuse type lesions than in the intestinal type (P = 0.022). The patients with p16+/pRb-/cyclin D1-/CDK4- or p16-/pRb+/cyclin D1-/CDK4- tumors demonstrated particularly poor survival. With multivariate survival analysis, only depth of invasion and TNM stage could be proven as independent predictors.
  
  
  CONCLUSIONS
  The Rb pathway is disrupted in the vast majority of gastric carcinomas. This study also identified specific immunohistochemical marker profiles for prognosis.
authors.affiliation: Department of Surgery, National Hospital Organization Sagamihara Hospital, Kanagawa, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kishimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mitomi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohkura
authors.forename: Hideki
authors.initials: H
authors.lastname: Kanazawa
authors.forename: Naoshi
authors.initials: N
authors.lastname: Fukui
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000556:secondary; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4