Mcm2, Geminin, and KI67 Define Proliferative State and are Prognostic Markers in Renal Cell Carcinoma

Abstract

Purpose: 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. Experimental Design: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, anMcm2 À 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.

The cell cycle and cancer

“…Moreover, Mcm2-7 expression levels are powerful prognostic indicators in diverse tumour types, including cancers of the lung, breast, kidney, bladder, prostate and ovary [71][72][73][74][75][76][77]. This finding is consistent with large-scale meta-analysis of cancer microarray data, which identified up-regulation of the MCM2-6 genes as a component of poor prognostic signatures [78].…”

Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma

“…With the development of (Meng et al, 2001;Padmanabhan et al, 2004) and ovarian serous neoplasms (Scott et al, 2004) chondrosarcoma (Helfenstein et al, 2004), oligodendroglial tumours (Wharton et al, 2001(Wharton et al, , 2004, oesophageal neoplasm (Going et al, 2002), renal cell carcinoma (Dudderidge et al, 2005), breast cancer (Gonzalez et al, 2004), endometrial carcinoma (Li et al, 2005) and thyroid carcinoma (Guida et al, 2005).…”

“…The clinical relevance of MCM proteins as proliferation markers has been investigated immunohistochemically in several different malignant tumours (Freeman et al, 1999), for example, non-smallcell lung cancer (Ramnath et al, 2001), prostate cancer (Meng et al, 2001;Padmanabhan et al, 2004), oral squamous cell carcinoma (Kodani et al, 2003), chondrosarcoma (Helfenstein et al, 2004), oligodendroglial tumours (Wharton et al, 2001(Wharton et al, , 2004, oesophageal neoplasm (Going et al, 2002), renal cell carcinoma (Dudderidge et al, 2005), breast cancer (Gonzalez et al, 2004), endometrial carcinoma (Li et al, 2005) and thyroid carcinoma (Guida et al, 2005). Most of these studies focused on the detection of MCM2 (Freeman et al, 1999;Chatrath et al, 2003;Davidson et al, 2003;Kodani et al, 2003;Scott et al, 2004).…”

Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer

“…Mcm2, geminin and Ki67 Immunohistochemical staining for Mcm2, geminin and Ki67 was performed as described (Dudderidge et al, 2005). Incubation without primary antibody was used as a negative control, and colonic epithelial sections were used as positive controls.…”

“…The constituents of the pre-RC can be regarded as relay stations coupling growth regulatory pathways with DNA replication . We and others have demonstrated in a range of different tumour types that dysregulation of the MCM proteins is an early event in tumourigenesis and have exploited these biomarkers in primary diagnosis, tumour surveillance and prognosis (Williams et al, 1998Stoeber et al, 1999Stoeber et al, , 2002Wharton et al, 2001Wharton et al, , 2004Davies et al, 2002;Going et al, 2002;Gonzalez et al, 2003;Kruger et al, 2003;Padmanabhan et al, 2004;Dudderidge et al, 2005;Korkolopoulou et al, 2005;Shetty et al, 2005). These studies have established that the superior sensitivity of MCM proteins over the standard proliferation marker Ki67 resides in the fact that these biomarkers identify not only cycling cells but also non-cycling cells with proliferative potential ).…”