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Minichromosome maintenance complex component 6 (MCM6) expression correlates with histological grade and survival in endometrioid endometrial adenocarcinoma

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Abstract

Minichromosome maintenance complex component 6 (MCM6) is involved in initiating DNA replication and is upregulated during licensed G0 phase of the cell cycle. This early expression permits its labeling of more proliferating cells than those by Ki-67. Here using a cohort of 89 endometrioid adenocarcinoma, we report findings made on the prognostic value of MCM6 based on immunohistochemical labeling index (LI) of the protein in comparison with that of Ki67 as no such information is currently available. Additionally, we examined the prognostic values of these markers based on their mRNA expression using a cohort of uterine corpus endometrial carcinoma (UCEC, n = 307) taken from The Cancer Genome Atlas (TCGA) database. Our evidence indicated the presence of a positive correlation between the LI of MCM6 and the histological grade of endometrioid endometrial adenocarcinoma (grade I, 66.7%; grade II, 75.3%; grade III, 81.4%; p < 0.001) and an inverse correlation between the LI of MCM6 and the overall and progression-free survival (p = 0.02 for both). The LI of Ki-67 correlated with grade (p < 0.001), but not survival. The MCM6 and Ki-67 inter-observer intra-class correlation coefficients were excellent: 0.84 (95% confidence interval, 0.83–0.91) and 0.84 (0.77–0.90), respectively. For in silico analyses of the TCGA cohort, both univariate and multivariate Cox analyses (p = 0.003 and p = 0.03, respectively) revealed high MCM6 mRNA Z-scores associated with reduced overall survival. This association was absent for Ki-67. MCM6 is thus a highly reproducible marker of poor prognosis in endometrial cancer. Evaluation of MCM6 should thus be considered in daily practice for risk stratification.

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Acknowledgements

The authors thank all members of Pathology Departments of CHRU (Nancy) and Institut de Cancérologie de Lorraine (Vandoeuvre-lès-Nancy) for their technical support and Ms. Magali LEFEBVRE and Delphine CLABAUT for their advices.

Results are in part generated by the data extracted from the database of TCGA Research Network: http://cancergenome.nih.gov/.

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Author notes

  1. Judicaël Hotton and Mikaël Agopiantz contributed equally to this work.

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, CHRU de Nancy, Nancy, France

    Judicaël Hotton & Olivier Morel

  2. INSERM U954, Université de Lorraine, Vandœuvre-lès-Nancy, France

    Judicaël Hotton, Mikaël Agopiantz, Hélène Busby-Venner, Jean-Louis Guéant, Jean-Michel Vignaud, Shyue-Fang Battaglia-Hsu & Guillaume Gauchotte

  3. Department of Medical Gynecology, CHRU de Nancy, Nancy, France

    Mikaël Agopiantz

  4. Department of Pathology, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France

    Agnès Leroux

  5. Department of Radiotherapy, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France

    Claire Charra-Brunaud

  6. Department of Pathology, CHRU de Nancy, Nancy, France

    Béatrice Marie, Hélène Busby-Venner, Jean-Michel Vignaud & Guillaume Gauchotte

  7. Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, CHRU de Nancy, Vandœuvre-lès-Nancy, France

    Jean-Louis Guéant

  8. Service d’Anatomie et Cytologie Pathologiques, Hôpital Central, CHRU de Nancy, 29, avenue du Maréchal De Lattre de Tassigny, 54000, Nancy, France

    Guillaume Gauchotte

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  1. Judicaël Hotton
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Correspondence to Guillaume Gauchotte.

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The experiments reported here were carried out according to the Declaration of Helsinki principles and in agreement with the French laws on biomedical research (institutional review board n°DC2008-459; CNIL declaration n°1209171).

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Electronic supplementary material

Supplementary Figure S1

MCM6 and Ki-67 labeling index and p53 status. (A) Significant correlation between overexpression of MCM6 staining and p53 mutated status (p = 0.003). (B) No association between Ki-67 labeling expression and p53 status (p = 0.23) (boxplots; Wilcoxon tests). (JPEG 42 kb)

High resolution image (TIFF 1254 kb)

Supplementary Figure S2

MCM6 and Ki-67 labeling index and microsatellite instability (MSI). (A) Significant correlation between overexpression of MCM6 staining and microsatellite instability (p = 0.03). (B) No association between Ki-67 labeling expression and tumors showing loss of MSH6 and/or PMS2 (p = 0.41) (boxplots; Wilcoxon tests). (JPEG 42 kb)

High resolution image (TIFF 1254 kb)

Supplementary Figure S3

Correlation curve between marker of proliferation Ki-67 (Ki-67), and minichromosome maintenance complex component 6 (MCM6) expression in endometrioid endometrial adenocarcinoma (rho = 0.55, p < 0.001) (Spearman’s correlation test). (GIF 154 kb)

High resolution image (TIFF 1002 kb)

Supplementary Figure S4

Survival analyses in the uterine corpus endometrioid carcinoma cohort of TCGA. Kaplan-Meier curves with log-rank tests. (A) Correlation between minichromosome maintenance complex component 6 (MCM6) mRNA Z-score and overall survival (p = 0.04) (threshold: 75th percentile [0.45]). (B) Lack of significant correlation between marker of proliferation Ki-67 (Ki-67), mRNA Z-score and overall survival (p = 0.2)(threshold: 75th percentile [0.50]). (JPEG 65 kb)

High resolution image (TIFF 1272 kb)

Supplementary Figure S5

Expression of minichromosome maintenance complex component 6 (MCM6) sorted by molecular subgroups (A) (p < 0.001). Expression of marker of proliferation Ki-67 (Ki-67), sorted by molecular subgroups (B) (p < 0.001) (boxplots; Kruskal-Wallis tests). (JPEG 52 kb)

High resolution image (TIFF 1272 kb)

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Hotton, J., Agopiantz, M., Leroux, A. et al. Minichromosome maintenance complex component 6 (MCM6) expression correlates with histological grade and survival in endometrioid endometrial adenocarcinoma. Virchows Arch 472, 623–633 (2018). https://doi.org/10.1007/s00428-017-2278-9

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