Tissue microarray molecular profiling of early, node-negative adenocarcinoma of the rectum: a comprehensive analysis.
OBJECTIVE
Early-stage adenocarcinoma of the rectum treated with curative intent has a favorable overall prognosis; however, 20%-30% of the patients recur, and the majority ultimately die of disease. Recurrence and tumor-related mortality may be attributable to molecular abnormalities in primary tumors accounting for their more aggressive biological behavior. This study evaluates such molecular phenotypes with regard to cell cycle regulation and proliferation and determines their significance for patient outcome.


METHODS
One hundred patients with primary T(2-3), N(0) adenocarcinoma of the rectum uniformly treated by surgery alone were studied. Core biopsies of pathological specimens were assembled on tissue microarrays, and expression of p53, mdm-2, p21, Bcl-2, p27, cyclin D1, and Ki-67 was analyzed by immunohistochemistry. Molecular profiles were correlated with disease-free (DFS) and disease-specific survival (DSS).


RESULTS
Despite previously described prognostic relevance of some of the investigated molecules in analyses where different stages of colorectal cancer were included, none of the cell cycle-regulatory or proliferation-related markers was associated with recurrence or survival. However, patients with tumors demonstrating down-regulation of p27, a cyclin-dependent kinase inhibitor and tumor suppressor gene associated with development of metastases, showed a trend toward reduced DFS and DSS (P = 0.06 and P = 0.07, respectively).


CONCLUSIONS
In this homogeneous group of patients with early-stage, node-negative adenocarcinoma of the rectum uniformly treated by surgery alone, the investigated cell cycle-regulatory and proliferation-associated proteins appear to have no prognostic significance. However, down-regulation of p27 appears to be associated with a trend toward reduced DFS and DSS, which suggests further investigation of other p27-related pathways potentially relevant for metastatic disease.
Hoos
Axel
A
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Nissan
Aviram
A
Stojadinovic
Alexander
A
Shia
Jinru
J
Hedvat
Cyrus V
CV
Leung
Denis H Y
DH
Paty
Philip B
PB
Klimstra
David
D
Cordon-Cardo
Carlos
C
Wong
W Douglas
WD
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins; D040081:Protein Array Analysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012004:Rectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2