p27 downregulation and metallothionein overexpression in gastric cancer patients are associated with a poor survival rate.
OBJECTIVE
As a significant number of curatively treated gastric cancer patients will ultimately relapse, there is an urgent need to investigate new prognostic markers for identification of high-risk patients. In this study, we investigated the possible role of molecular markers involved in cell cycle regulation (B1 and D3 cyclins, and p27) and cell protection (metallothionein, MT) in predicting tumor behavior and clinical outcome in gastric cancer patients.


METHODS
Analysis of the above indicators was performed by immunohistochemistry on 73 gastric cancer patient samples and 25 normal gastric mucosa specimens.


RESULTS
Normal gastric mucosa cells displayed low expressions of B1 and D3 cyclins and MT, and intense p27 staining. Conversely, gastric tumor cells showed higher cyclin D3 and MT, and lower p27 expressions. B1 cyclin expressions were not different between normal and tumor tissue. p27 and MT expressions were altered in almost all cancer samples, and were strongly correlated with tumor progression. Advanced extent of the primary tumor, nodal metastasis, low p27, and high MT expressions were the best combination of variables for prediction of poor clinical outcome. Each marker predicted outcome better than staging based on tumor-node (TNM) system. Survival and recurrence rates decreased as molecular alterations increased. Finally, molecular profile determination correctly predicted the prognosis in patients with same TNM stage.


CONCLUSIONS
p27 and MT expressions strongly correlated with clinical outcome allowing to identify an unfavorable group of patients that may benefit from tailored treatments. The role of B1 and D3 cyclins in gastric cancer remains to be elucidated.
Galizia
Gennaro
G
Division of Surgical Oncology, F. Magrassi-A. Lanzara Department of Clinical and Experimental Medicine and Surgery, Second University of Naples School of Medicine, Naples, Italy. gennaro.galizia@unina2.it
Ferraraccio
Francesca
F
Lieto
Eva
E
Orditura
Michele
M
Castellano
Paolo
P
Imperatore
Vincenzo
V
La Manna
Giovanni
G
Pinto
Margherita
M
Ciardiello
Fortunato
F
La Mura
Anna
A
De Vita
Ferdinando
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D019926:Cyclin B / Q000032:analysis; D056744:Cyclin B1; D056743:Cyclin D3; D016213:Cyclins / Q000032:analysis; D015536:Down-Regulation; D005260:Female; D005753:Gastric Mucosa / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008668:Metallothionein / Q000032:analysis*; D008875:Middle Aged; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis*; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000401:mortality* / Q000473:pathology; D015996:Survival Rate; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; C534699:CCNB1 protein, human; C534696:CCND3 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D056743:Cyclin D3; D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen; D008668:Metallothionein