Promoter hypermethylation of tumor suppressor genes in urine from patients with cervical neoplasia

We examined the feasibility of using detection of high-risk human papillomavirus (HPV) DNA in combination with the presence of aberrantly methylated genes (DAPK1, RARB, TWIST1, and CDH13) for urine-based cervical cancer screening. Urine samples from 129 Senegalese women, aged 35 years or older, 110 with (same day) biopsy-proven cervical neoplasia [cervical intraepithelial neoplasia grade 1 (CIN-1): n = 9; CIN-2-3/carcinoma in situ (CIS): n = 29; invasive cervical cancer (ICC): n = 721, and 19 without cervical neoplasia on biopsy were examined. Hypermethylation of at least one of the four genes identified 62% of ICC and 28% of CIN-2-3/CIS and was present in only 4% of CIN-1 or normal urines. High-risk HPV DNA was detected in urine in 70% of those with biopsy-proven ICC, 59% of those with CIN2-3/CIS on biopsy, 44% of those with CIN-1 on biopsy, and only 11% of women negative for cervical neoplasia on biopsy. Urine-based detection of either high-risk HPV or hypermethylation of any of the four genes identified 84% of ICC, 64% of CIN-2-3/CIS, 44% of CIN-1, but only 19% of women negative for cervical neoplasia. The sensitivity for detection of CIN-2-3/CIS/ICC by high-risk HPV DNA or aberrant DNA methylation of four genes seems to be comparable to that of an exfoliated cervical cytology. This study shows the potential feasibility of using molecular markers detected in urine for cervical cancer screening.