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Gynecol Oncol. 2018 Sep;150(3):545-551. doi: 10.1016/j.ygyno.2018.06.014. Epub 2018 Jun 28.

Methylation of the hsa-miR-124, SOX1, TERT, and LMX1A genes as biomarkers for precursor lesions in cervical cancer.

Author information

1
Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.
2
Department of Radiology and Oncology, School of Medicine, University of São Paulo, São Paulo, Brazil; ICESP - Cancer Institute of the State of São Paulo, São Paulo, Brazil.
3
Department of Pathology, Barretos Cancer Hospital, Barretos, Brazil.
4
DASA - Diagnostics of America, Barueri, Brazil.
5
Department of Prevention, Barretos Cancer Hospital, Barretos, Brazil.
6
Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil; Life and Health Sciences Research Institute, ICVS, School of Medicine, Minho University, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal; Department of Pathology, LIM14, School of Medicine, University of São Paulo, São Paulo, Brazil.
7
Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil; A.C. Camargo Cancer Center, São Paulo, Brazil. Electronic address: mdfregnani@terra.com.br.

Abstract

OBJECTIVES:

The methylation profile of genes in precursor lesions in cervical cancer was characterized to improve screening techniques for high-grade intraepithelial neoplasia.

METHODS:

A total of 447 cervical cytology samples obtained from women who underwent colposcopy were examined. The cases were distributed as follows: (1) cervices without cervical intraepithelial neoplasia (CIN; n = 152); (2) cervices with a CIN grade of 1 (CIN 1; n = 147); and (3) cervices with a CIN grade of 2 or 3 (CIN 2/3; n = 148). The methylation pattern for a panel of 15 genes was analysed by quantitative methylation-specific PCR (qMSP) and compared between the groups (≤CIN 1 vs. CIN 2+).

RESULTS:

In the validation set, seven genes presented significantly different methylation profiles according to diagnosis, namely, DAPK1 (p = 0.001), EPB41L3 (p = 0.001), HIC1 (p = 0.028), hsa-miR-124-2 (p = 0.001), LMX1A (p = 0.001), SOX1 (p = 0.001), and TERT (p = 0.001). Six genes showed a significant increase in the frequency of methylation in the presence of hr-HPV, namely, DAPK1 (p = 0.001), EPB41L3 (p = 0.001), hsa-miR-124-2 (p = 0.001), LMX1A (p = 0.001), SOX1 (p = 0.001), and TERT (p = 0.001). The methylation of the hsa-miR-124 gene showed sensitivity and specificity (86.7% and 61.3%, respectively) similar to that of the HPV test (91.3% and 50.0%, respectively). The independent factors associated with the diagnosis of CIN 2+ and the methylation of the hsa-miR-124-2 (OR = 5.1), SOX1 (OR = 2.8), TERT (OR = 2.2), and LMX1A (OR = 2.0) genes were a positive test for hr-HPV (odds ratio [OR] = 5.5).

CONCLUSIONS:

Hypermethylation of the hsa-miR-124-2, SOX1, TERT, and LMX1A genes may be a promising biomarker for precursor lesions in cervical cancer regardless of the hr-HPV status.

KEYWORDS:

Cervical cancer prevention; Cervical cytology; Cervical intraepithelial neoplasia; DNA methylation; Human papillomavirus; Tumour suppressor genes

PMID:
29960712
DOI:
10.1016/j.ygyno.2018.06.014
[Indexed for MEDLINE]

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