Abnormal expression of p16(INK4a), cyclin D1, cyclin-dependent kinase 4 and retinoblastoma protein in gastric carcinomas.
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.
Kishimoto
Ichiro
I
Department of Surgery, National Hospital Organization Sagamihara Hospital, Kanagawa, Japan.
Mitomi
Hiroyuki
H
Ohkura
Yasuo
Y
Kanazawa
Hideki
H
Fukui
Naoshi
N
Watanabe
Masahiko
M
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
D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4