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

• Published in: Gynecologic oncology Vol. 150; no. 3; pp. 545 - 551
• Main Authors: Rogeri, Caroline Domingues, Silveira, Henrique César Santejo, Causin, Rhafaela Lima, Villa, Luisa Lina, Stein, Maíra Degiovani, de Carvalho, Ana Carolina, Arantes, Lídia Maria Rebolho Batista, Scapulatempo-Neto, Cristovam, Possati-Resende, Júlio César, Antoniazzi, Márcio, Longatto-Filho, Adhemar, Fregnani, José Humberto Tavares Guerreiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2018; Elsevier 1
• Subjects: Adult; Biomarkers; Cervical cancer prevention; Cervical cytology; Cervical Intraepithelial Neoplasia; Ciências Médicas; DNA Methylation; Early Detection of Cancer; Female; Genetic; Human papillomavirus; Humans; Medicina Básica; MicroRNAs; Middle Aged; Papillomaviridae; Papillomavirus Infections; Promoter Regions; Science & Technology; Sensitivity and Specificity; SOXB1 Transcription Factors; Telomerase; Transcription Factors; Tumor; Tumour suppressor genes; Uterine Cervical Neoplasms; Cervical cytology; DNA methylation; Cervical cancer prevention; Human papillomavirus; Tumour suppressor genes; Cervical intraepithelial neoplasia
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2018.06.014

The methylation profile of genes in precursor lesions in cervical cancer was characterized to improve screening techniques for high-grade intraepithelial neoplasia. 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+). 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). 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. •The hypermethylation of hsa-miR-124, SOX1, TERT and LMX1A is correlated with CIN 2+.•The sensitivity of hsa-miR-124 for detection of CIN 2+ was similar to the HPV test.•Methylation of hsa-miR-124, SOX1, TERT and LMX1A was an independent predictor of CIN 2+.•Methylation of certain genes and hr-HPV infection showed a synergistic effect.