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

Abstract

Minichromosome maintenance protein 6 (MCM6) is one of six proteins of the MCM family which are involved in the initiation of DNA replication and thus represent a marker of proliferating cells. Since the level of cell proliferation is the most valuable predictor of survival in mantle cell lymphoma (MCL), we investigated lymph node biopsy specimens from 70 patients immunohistochemically with a monoclonal antibody against MCM6. The percentage of MCM6 expressing lymphoma cells ranged from 12.0 to 95.6%, with a mean of 61.0%, and was significantly higher than the percentage of Ki-67-positive cells (Po0.0001). Surprisingly, the ratio of MCM6-positive cells to Ki-67-positive cells was higher than in normal stimulated peripheral blood mononuclear cells, indicating a cell early G1-phase arrest in MCL. A high MCM6 expression level of more than 75% positive cells was associated with a significantly shorter overall survival time (16 months) compared to MCL with a low MCM6 expression level of less than 25% (no median reached, Po0.0001). Multivariate analysis revealed MCM6 to be an independent predictor of survival that is superior to the international prognostic factor and the Ki-67 index. Therefore, aside from gene expression profiling, immunohistochemical detection of MCM6 seems to be the most promising marker for predicting the outcome in MCL.

Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumours: relationship with cell cycle regulators and prognostic implications

“…However, and in keeping with our previous observations in muscle-invasive urothelial carcinomas (Korkolopoulou et al, 2005), median values of MCM-5 were significantly higher than those of Ki-67 in ovarian carcinomas as well as in LMP tumours. It has been claimed that MCMs represent a potentially more accurate means of determining the proliferative fraction within a tumour than the conventional proliferation indices probably because the latter fail to label cells in early G 1 (Osaki et al, 2002;Korkolopoulou et al, 2005;Schrader et al, 2005). However, the discrepancy between MCMLIs and Ki-67 LI might be a reflection of the fact that Ki-67 is downregulated early in the differentiation programme, whereas MCMs are downregulated later, when the cells adopt a terminally differentiated phenotype (Eward et al, 2004;Kingsbury et al, 2005).…”

Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion

“…Clinical follow-up data of 20 MB patients were analyzed, as no survival data are available for the others. cell lymphoma patients (Schrader et al, 2005). In this study, we simultaneously examined the expression of multiple MCMs in MB.…”

Allelic genotyping reveals a hierarchy of genomic alterations in mantle cell lymphoma associated to cell proliferation

“…However, this translocation alone is not sufficient to promote MCL development but additional genomic alterations appear to be essential for malignant transformation [30]. To identify secondary genetic alterations involved, several groups have applied different techniques such as cytogenetic analysis, comparative genomic hybridization or DNA microarray [1,5,11,19,28,44]. In this study, we used a comprehensive method of allelotyping for the detection of genomic gains and losses in MCL [24].…”

“…Blastoid variants of MCL have a high incidence of p53 gene mutations [20,21], p16 INK4a deletions or hypermethylation [14,25,36]. In addition, shorter survival among MCL patients has been correlated with overexpression of c-myc [32] and a high cell proliferation index as measured by immunostaining of other proliferation-associated transcription factors [44]. Applying FISH analysis, a deletion of the 11q14-q24 chromosomal region including the ATM gene could be identified in 46% of MCL cases [45].…”

“…Comparative genomic hybridization (CGH) and arraybased genomic analysis revealed amplifications in 3q, 7p, 8q, 12q, 18q, 9q and deletions in 6q, 1p, 11q, 10p, 17p, 9p, and 13q as frequent secondary genetic alterations [1,5,19,28,41,44]. Those genetic alterations were more frequently found in blastoid than in classical MCL [4,31].…”