MCM2 Is an Independent Predictor of Survival in Patients With Non–Small-Cell Lung Cancer

Ramnath, Nithya; Hernandez, Francisco; Tan, Dongfeng; Huberman, Joel A.; Natarajan, Nachimuthu; Beck, Amy; Hyland, Andrew; Todorov, Ivan; Brooks, John S.; Bepler, Gerold

doi:10.1200/jco.2001.19.22.4259

Cited by 115 publications

(104 citation statements)

References 33 publications

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“…Nevertheless, the Ki-67 and MCM6 indices showed a good correlation (Figure 3, Po0.0001). These data are in line with others (Ramnath et al, 2001;Helfenstein et al, 2004), indicating that the ratio of MCM6-and Ki-67-positive cells is larger in MCL than the Ki-67 expressing cells. Blastoid variants usually have a more aggressive clinical behaviour than classical types, and the proliferation indices in the blastoid subtypes are usually higher (Schrader et al, 2004).…”

Section: Discussionsupporting

confidence: 92%

“…The median survival times for the quartiles are listed in Table 3. In accordance with Ramnath et al (2001), we analysed the MCM expression in four categories. Patients with an MCM6 expression level of lower than 25% had not yet reached a median survival, in contrast to 38.2 months for the group with 25 -50%, 30 months for the group with 50 -75% and 16.0 months for patients with more than 75% ( Figure 5 and Table 3, Po0.0001).…”

Section: Resultsmentioning

confidence: 99%

“…In a large study, Ramnath et al (2001) examined 221 patients with lung cell cancer immunohistochemically for MCM2 expression and found MCM2 expression to be an independent prognostic factor for survival. In this study, patients with MCM2 expression in less than 25% of the tumour cells had a significantly better prognosis than patients with tumours with a higher MCM2 index.…”

Section: Discussionmentioning

confidence: 99%

“…Kaplan -Meier analysis showed significant differences in the overall survival time in different quartiles ( Figure 4, Table 3, Po0.0001). Second, for the Kaplan -Meier analysis, we chose different MCM6 expression levels according to the categories of Ramnath et al (2001). In the group under 25% MCM6-positive cells, the median overall survival time was despite the long followup time not reached, indicating that this group of patients has an excellent prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

et al. 2005

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2005

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Myc and the Replicative CMG Helicase: The Creation and Destruction of Cancer

Reed

Alexandrow

2020

BioEssays

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Myc‐driven tumorigenesis involves a non‐transcriptional role for Myc in over‐activating replicative Cdc45‐MCM‐GINS (CMG) helicases. Excessive stimulation of CMG helicases by Myc mismanages CMG function by diminishing the number of reserve CMGs necessary for fidelity of DNA replication and recovery from replicative stresses. One potential outcome of these events is the creation of DNA damage that alters genomic structure/function, thereby acting as a driver for tumorigenesis and tumor heterogeneity. Intriguingly, another potential outcome of this Myc‐induced CMG helicase over‐activation is the creation of a vulnerability in cancer whereby tumor cells specifically lack enough unused reserve CMG helicases to recover from fork‐stalling drugs commonly used in chemotherapy. This review provides molecular and clinical support for this provocative hypothesis that excessive activation of CMG helicases by Myc may not only drive tumorigenesis, but also confer an exploitable “reserve CMG helicase vulnerability” that supports developing innovative CMG‐focused therapeutic approaches for cancer management.

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Phase 2 randomized study of enzastaurin (LY317615) for lung cancer prevention in former smokers

Gray

Altiok

Alexandrow

et al. 2012

Cancer

Self Cite

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BACKGROUND Chemoprevention for lung cancer with neutraceuticals or anti-inflammatory agents has had mixed clinical benefit. Novel targeted agents hold the promise of greater efficacy and selectivity. Here, we evaluated enzastaurin, a selective PKC-β inhibitor with antiproliferative and proapoptotic properties in former smokers. METHODS The primary objective was to compare the average fraction of Ki-67 stained cells (labeling index [LI]) in bronchial biopsies collected before and after treatment. Subjects were randomized (2:1) to 6 months of daily oral enzastaurin (500mg) or placebo. Stratification was based on morphology, history of lung cancer, and airway obstruction. RESULTS In pretrial investigations, we established the rationale for PKC-β inhibition and pathway interrogation in premalignant lesions and early stage lung cancer. In the intent-to-treat analysis, of 40 subjects randomized, there was no significant difference in the pre/post-treatment change of the Ki-67 LI between the enzastaurin and placebo groups (p = 0.53). Six subjects discontinued enzastaurin (n=4, AEs: abdominal distension, DVT, hyponatremia, and rash; n=2, subject decision) and one placebo (noncompliance). Two subjects had ≥1 serious AEs (bradycardia, DVT, and hypotension). CONCLUSIONS This represents the first chemoprevention trial with a non-FDA-approved, oral, small-molecule targeted agent. Although the primary endpoint was not met, enzastaurin was found to be tolerable for 6 months by 75% of subjects with a suggestion of response in a subset analysis restricted to metaplastic or dysplastic lesions.

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MCM2 Is an Independent Predictor of Survival in Patients With Non–Small-Cell Lung Cancer

Cited by 115 publications

References 33 publications

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

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

Myc and the Replicative CMG Helicase: The Creation and Destruction of Cancer

Phase 2 randomized study of enzastaurin (LY317615) for lung cancer prevention in former smokers

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