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Aberrant DNA methylation of DLX 4 and SIM 1 is a predictive marker for disease progression of uterine cervical low‐grade squamous intraepithelial lesion
Author(s) -
Sakane Junichi,
Taniyama Kiyomi,
Miyamoto Kazuaki,
Saito Akihisa,
Kuraoka Kazuya,
Nishimura Toshinao,
Sentani Kazuhiro,
Oue Naohide,
Yasui Wataru
Publication year - 2015
Publication title -
diagnostic cytopathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.417
H-Index - 65
eISSN - 1097-0339
pISSN - 8755-1039
DOI - 10.1002/dc.23256
Subject(s) - dna methylation , methylation , medicine , cytology , squamous intraepithelial lesion , cervical intraepithelial neoplasia , cancer research , gene , gastroenterology , cancer , gene expression , cervical cancer , pathology , biology , biochemistry
Background A few uterine cervical low‐grade squamous intraepithelial lesions (LSILs) are known to progress with high‐risk human papillomavirus (hrHPV). Methods One hundred and thirteen patients were classified into four groups according to their cervical cytology, hrHPV infection, and follow up. Cytology samples were examined for aberrant DNA methylation of DLX4 and SIM1 genes and protein expressions. CaSki cells were treated with 5‐Aza‐2′‐deoxycytidine (5‐aza‐dC). Results Group 1 was negative for intraepithelial lesions or malignancies. LSIL in group 2 showed a continuance of LSIL for longer than 365 days and LSIL in group 3 showed an upgrading to high‐grade (H) SIL or higher (HSIL+) within 365 days of LSIL diagnosis. Group 4 was squamous cell carcinoma. All but group 1 were infected with hrHPV. Significant differences existed in the frequency of DNA methylation between groups 2 and 3 (p = 0.044), between groups 3 and 4 (p = 0.020) for DLX4, and between groups 1 and 3 (p = 0.0003), and groups 2 and 3 (p = 0.005) for the SIM1 gene. DLX4 protein expression was significantly reduced in the DLX4 methylation positive tissues (p = 0.008). The 5‐aza‐dC treatment restored DLX4 mRNA expressions of CaSki cells (p < 0.005). The LSIL cases with DNA methylation of the SIM1 gene, or both genes, progressed faster to HSIL+ than did the others (p = 0.033 and p = 0.045, respectively). Conclusion Aberrant DNA methylation of the DLX4 and SIM1 genes should be a novel progression marker for uterine cervical LSIL with hrHPV infection. Diagn. Cytopathol. 2015;43:462–470. © 2015 Wiley Periodicals, Inc.