Article

p16(INK4A), CDC6, and MCM5: predictive biomarkers in cervical preinvasive neoplasia and cervical cancer

Department of Pathology, Coombe Women's Hospital, Dublin 8, Ireland.
Journal of Clinical Pathology (Impact Factor: 2.55). 06/2005; 58(5):525-34. DOI: 10.1136/jcp.2004.018895
Source: PubMed

ABSTRACT To analyse and compare expression patterns of three potential biomarkers-p16(INK4A), CDC6, and MCM5-and evaluate their use as predictive biomarkers in squamous and glandular cervical preinvasive neoplasia.
Immunocytochemical analysis of p16(INK4A), MCM5, and CDC6 expression was performed on 20 normal, 38 cervical intraepithelial neoplasia 1 (CIN1), 33 CIN2, 46 CIN3, 10 squamous cell carcinoma, 19 cervical glandular intraepithelial neoplasia (cGIN), and 10 adenocarcinoma samples. Staining intensity was assessed using a 0-3 scoring system. p16(INK4A), MCM5, and CDC6 expression was also examined in ThinPrep slides exhibiting mild, moderate, and severe dyskaryosis. Human papillomavirus (HPV) was detected using a modified SYBR green assay. Fluorogenic polymerase chain reaction (PCR) and solution phase PCR were used for specific HPV typing.
All three markers showed a linear correlation between expression and grade of dysplasia. p16(INK4A) and MCM5 protein expression was upregulated in all grades of squamous and glandular dysplasia. CDC6 protein was preferentially expressed in high grade lesions and in invasive squamous cell carcinoma.
p16(INK4A) expression was closely associated with high risk HPV infection-all grades of squamous and glandular cervical lesions were immunohistochemically positive. MCM5 staining intensity was independent of high risk HPV infection, highlighting its potential as a biomarker in both HPV dependent and independent cervical dysplasia. CDC6 may be a biomarker of high grade and invasive lesions of the cervix, with limited use in low grade dysplasia. p16(INK4A) was the most reliable marker of cervical dysplasia. Combinations of dysplastic biomarkers may be useful in difficult diagnostic cases.

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    • "Recent researches highlight the role of p16, as an extremely sensitive marker for cervical epithelial dysplasia and high-risk HPV-type related neoplasia [9– 11, 29, 30], and for predicting SIL progression [13] [14]. "
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    • "Cdc7-Dbf4 is therefore an essential cell cycle regulator that is also important for genome integrity in the response to DNA damage or replication fork arrest. Previous studies examining proteins required for the initiation of DNA replication have shown that Cdc6, Mcm2, Mcm5, and Cdt1 are variously up-regulated in cancers of the bladder, colon, cervix, and lung [21] [22] [23] [24] [25] [26] [27] [28]. CDC7 mRNA expression is also altered in some cancer cell lines and primary tumors [29], and furthermore, somatic CDC7 mutations were identified in colorectal and gastric carcinomas through comprehensive kinome screens of human tumors [30] [31]. "
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    • "Differentially expressed genes thus identified also represent possible targets for TNA-based therapy [36]. Overexpression of p16 INK4a (a Cdk inhibitor involved in cell cycle regulation) [37], MYBL2 [38] and the cell cycle regulatory proteins Cdt1and Cdc6 [39] have all been reported in cervical dysplasia and carcinoma. Nevertheless, this overexpression is likely the result of HPV E7 interaction with pRB 107 and thus presents possible secondary targets for TNA therapy [40] [41]. "
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