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Methylation of p16INK4a is a non-rare event in cervical intraepithelial neoplasia

 Suki Kang  ;  Jungsik Kim  ;  Hong Bae Kim  ;  Jung Won Shim  ;  Eunji Nam  ;  Sung Hoon Kim  ;  Hee Jung Ahn  ;  Yoon Pyo Choi  ;  Boxiao Ding  ;  Kijun Song  ;  Nam Hoon Cho 
 DIAGNOSTIC PATHOLOGY, Vol.15(2) : 74-82, 2006 
Journal Title
Issue Date
Base Sequence ; Case-Control Studies ; Cervical Intraepithelial Neoplasia/genetics* ; Cervical Intraepithelial Neoplasia/metabolism* ; Cervical Intraepithelial Neoplasia/pathology ; Cervical Intraepithelial Neoplasia/virology ; CpG Islands ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; DNA Methylation* ; DNA Primers/genetics ; DNA, Neoplasm/genetics* ; DNA, Neoplasm/metabolism* ; Female ; Gene Silencing ; Genes, p16* ; Humans ; Immunohistochemistry ; Molecular Sequence Data ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Papillomaviridae/classification ; Papillomaviridae/isolation & purification ; Polymerase Chain Reaction ; Uterine Cervical Neoplasms/genetics* ; Uterine Cervical Neoplasms/metabolism* ; Uterine Cervical Neoplasms/pathology ; Uterine Cervical Neoplasms/virology
p16INK4a ; methylation-specific PCR (MSP) ; pyrosequencing ; immunohistochemistry (IHC) ; cervix intraepithelial neoplasia (CIN)
The cell cycle inhibitor, p16INK4a may be a useful surrogate biomarker of cervical intraepithelial neoplasia (CIN); however, there is currently no consensus of p16INK4a genetic alterations throughout the multiple step process of CIN. Our goal was to identify the methylation frequency of p16INK4a in each step of CIN that is associated with human papillomavirus (HPV) infection, using several different detection methods of p16INK4a methylation to correlate the data. The present study included a total of 43 patients, including 38 with CIN, and 5 normal patients. Three different methods were used to detect hypermethylation of CpG islands, methylation-specific PCR (MSP) amplification of different primer sets of M1, M2, and M3, pyrosequencing of each forward primer region, and immunohistochemistry of p16INK4a. Analysis of MSP showed that 20 of the 38 CIN patients (52.6%) revealed hypermethylation in at least 1 primer set of the p16INK4a promoter. A complete loss of p16INK4a protein expression was observed in 11 cases (28.9%). There was no observed association of methylation of the p16INK4a gene with either CIN grading (P=0.0698) or HPV status (P=0.2811): specifically 42.9% (3/7) was found in CIN 1, 57.1% (8/14) in CIN 2, and 52.9% (9/17) in CIN 3. In concordance with immunohistochemistry results, hypermethylation of the p16INK4a promoter was significantly correlated with a lack of p16 protein expression (P=0.0145). All positive peaks from pyrosequencing matched the MSP results, which ranged from 6.3% to 24.5%. In conclusion, p16INK4a gene silencing during CIN was not determined to be a particularly rare event; however, it does not correlate with either HPV status or CIN grading.
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1. College of Medicine (의과대학) > Dept. of Biomedical Systems Informatics (의생명시스템정보학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Suki(강숙희) ORCID logo https://orcid.org/0000-0002-9957-3479
Kim, Sung Hoon(김성훈) ORCID logo https://orcid.org/0000-0002-1645-7473
Song, Ki Jun(송기준) ORCID logo https://orcid.org/0000-0003-2505-4112
Cho, Nam Hoon(조남훈) ORCID logo https://orcid.org/0000-0002-0045-6441
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