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

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 ON 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), LMXIA (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 613%, respectively) similar to that of the HPV test (913% 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 LMXIA (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 LMXIA genes may be a promising bio-marker for precursor lesions in cervical cancer regardless of the hr-HPV status.