Mcm2, Geminin, and KI67 define proliferative state and are prognostic markers in renal cell carcinoma.
OBJECTIVE
The origin licensing factors minichromosome maintenance 2 (Mcm2) and Geminin have recently been identified as critical regulators of growth and differentiation. Here we have investigated the regulation of these licensing factors together with Ki67 to further elucidate the cell cycle kinetics of renal cell carcinoma (RCC). Furthermore, we have examined the role of Ki67, Mcm2, and Geminin in disease-free survival after nephrectomy in patients with localized RCC.


METHODS
Tissue sections from 176 radical nephrectomy specimens were immunohistochemically stained with Mcm2, Geminin, and Ki67 antibodies. Labeling indices (LI) for these markers were compared with clinicopathologic parameters (median follow-up 44 months).


RESULTS
In RCC, Mcm2 is expressed at much higher levels than Ki-67 and Geminin, respectively [medians 41.6%, 7.3%, and 3.5% (P < 0.001)] and was most closely linked to tumor grade (P < 0.001). For each marker, Kaplan-Meier survival curves provided strong evidence that increased expression is associated with reduced disease-free survival time (P < 0.001). Additionally, an Mcm2-Ki67 LI identified a unique licensed but nonproliferating population of tumor cells that increased significantly with tumor grade (P = 0.004) and was also of prognostic value (P = 0.01). On multivariate analysis, grade, vascular invasion, capsular invasion, Ki67 LI >12%, and age were found to be independent prognostic markers.


CONCLUSIONS
Although Ki67 is identified as an independent prognostic marker, semiquantitative assessment is difficult due to the very low proliferative fraction identified by this marker. In contrast, Mcm2 identifies an increased growth fraction that is closely linked to grade, provides prognostic information, and is amenable to semiquantitative analysis in routine pathologic assessment.
Dudderidge
Tim J
TJ
Wolfson Institute for Biomedical Research, Department of Histopathology, London, United Kingdom.
Stoeber
Kai
K
Loddo
Marco
M
Atkinson
Geraldine
G
Fanshawe
Thomas
T
Griffiths
David F
DF
Williams
Gareth H
GH
D014408:Biomarkers, Tumor / Q000032:analysis*; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000032:analysis; D049109:Cell Proliferation; D005260:Female; D064248:Geminin; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2; D015999:Multivariate Analysis; D009687:Nuclear Proteins / Q000032:analysis; D011379:Prognosis; D012044:Regression Analysis; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C577995:GMNN protein, human; D064248:Geminin; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2