J Gynecol Oncol.  2012 Jan;23(1):11-15. 10.3802/jgo.2012.23.1.11.

Minichromosome maintenance 7 protein is a reliable biological marker for human cervical progressive disease

• Lobato S
• Tafuri A
• Fernandes
• Caliari MV
• Silva MX
• Xavier MA
• Vago AR

• KMID: 2177508
• DOI: http://doi.org/10.3802/jgo.2012.23.1.11

Abstract

OBJECTIVE
This study focused on comparing the expression levels of p16, Ki-67, and minichromosome maintenance 7 (MCM7) protein in normal and affected cervical epithelium to ascertain the biological significance of these markers in detecting progressive cervical disease.
METHODS
A quantitative and based on-scanning-microscopy analysis of the three markers expression was performed in normal and cervical intraepithelial neoplasia (CIN) I, II, and III tissues. p16 area as well as p16, Ki-67, and MCM7 positive cells or nuclei were evaluated according to their distribution and extent through the cervical epithelium.
RESULTS
A clear p16 over-expression was observed in all the dysplastic epithelium tissue samples. The quantitative analysis of p16 area as well as the number of p16 positive cells was able to better discriminate the CIN lesions grades than the usual semi-quantitative analysis. The average Ki-67 labeling indexes for the normal epithelium, CIN I, CIN II, and CIN III groups were 19.8%, 27.3%, 32.8%, and 37.1%, respectively, whereas the mean MCM7 labeling indexes for the correspondent grades were 27.0%, 30.4%, 50.5%, and 67.2%. The Ki-67 and MCM7 labeling indexes were closely correlated with the CIN histological grade, with higher labeling indexe values obtained from the more severe lesions (p<0.05), being the MCM7 labeling indexes the highest values in all the CIN categories (p<0.05).
CONCLUSION
We observed a good correlation among the p16, Ki-67, and MCM7 data. In addition, MCM7 demonstrated to be a more efficient and sensitive marker to assess disease progression in the uterine cervix.

Keyword

Cervical intraepithelial neoplasia; Genes p16; Immuno-fluorescence analysis; Ki-67 antigen; MCM7 protein

MeSH Terms

Biomarkers
Cervical Intraepithelial Neoplasia
Cervix Uteri
Disease Progression
Epithelium
Female
Humans
Ki-67 Antigen
Ki-67 Antigen

Figure

• 

  Fig. 1 Comparative immuno-fluorescent analysis of Ki-67, p16, and minichromosome maintenance 7 (MCM7) markers expression in human-cervical tissue-samples obtained by loop electrosurgical excision procedure (LEEP). The diagnoses were independently reviewed/confirmed by three certified pathologists. Positive Ki-67 and MCM7 cells show fluorescence-labeling confined to the nucleus (white), whereas p16-positive cells show nuclear/and/cytoplasmic labeling (green). Nuclei were immuno-labeled with propidium-iodide (red). CIN, cervical intraepithelial neoplasia.

Reference

1. Tsoumpou I, Arbyn M, Kyrgiou M, Wentzensen N, Koliopoulos G, Martin-Hirsch P, et al. p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer Treat Rev. 2009. 35:210–220.

2. Agoff SN, Lin P, Morihara J, Mao C, Kiviat NB, Koutsky LA. p16(INK4a) expression correlates with degree of cervical neoplasia: a comparison with Ki-67 expression and detection of high-risk HPV types. Mod Pathol. 2003. 16:665–673.

3. Kalof AN, Cooper K. p16INK4a immunoexpression: surrogate marker of high-risk HPV and high-grade cervical intraepithelial neoplasia. Adv Anat Pathol. 2006. 13:190–194.

4. Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000. 182:311–322.

5. Keating JT, Cviko A, Riethdorf S, Riethdorf L, Quade BJ, Sun D, et al. Ki-67, cyclin E, and p16INK4 are complimentary surrogate biomarkers for human papilloma virus-related cervical neoplasia. Am J Surg Pathol. 2001. 25:884–891.

6. Bell SP, Dutta A. DNA replication in eukaryotic cells. Annu Rev Biochem. 2002. 71:333–374.

7. Freeman A, Morris LS, Mills AD, Stoeber K, Laskey RA, Williams GH, et al. Minichromosome maintenance proteins as biological markers of dysplasia and malignancy. Clin Cancer Res. 1999. 5:2121–2132.

8. Brake T, Connor JP, Petereit DG, Lambert PF. Comparative analysis of cervical cancer in women and in a human papillomavirus-transgenic mouse model: identification of minichromosome maintenance protein 7 as an informative biomarker for human cervical cancer. Cancer Res. 2003. 63:8173–8180.

9. Nishihara K, Shomori K, Fujioka S, Tokuyasu N, Inaba A, Osaki M, et al. Minichromosome maintenance protein 7 in colorectal cancer: implication of prognostic significance. Int J Oncol. 2008. 33:245–251.

10. Mukherjee G, Muralidhar B, Bafna UD, Laskey RA, Coleman N. MCM immunocytochemistry as a first line cervical screening test in developing countries: a prospective cohort study in a regional cancer centre in India. Br J Cancer. 2007. 96:1107–1111.