Hypermethylation of two consecutive tumor suppressor genes, BLU and RASSF1A, located at 3p21.3 in cervical neoplasias

Objectives: Although initiated by human papillomavirus (HPV), cervical carcinogenesis demands other cofactors to shape its natural course. Epigenetic effects such as DNA methylation, are considered to contribute to carcinogenesis process. Methods: The methylation status of BLU and RASSF1A, as well as the HPV infection status, were assessed in a full spectrum of cervical neoplasia, including 45 low-grade squamous intraepithelial lesions (LSIL), 63 high-grade squamous intraepithelial lesions (HSIL), 107 squamous cell carcinomas (SCC), 23 adenocarcinomas (AC), and 44 normal control tissues. Results: The BLU was methylated in 76.9% of SCC, 57.4% of HSIL, 20.0% of LSIL and 12.5% of normal tissues (P <0.001). The RASSF1A was methylated in 15% of SCC, 17.5% of HSIL, but not in LSIL or normal tissues (P <0.001). In AC, 43.5% of patients showed BLU methylation and 26.1% RASSF1A methylation, significantly higher than the corresponding control frequencies of 12.5% (P = 0.005) and 0% (P = 0.001), respectively. There was an insignificant trend toward loss of BLU methylation with advancing clinical stages of SCC (84.8%, 67.7%, and 63.6% in stages I, II, and III/IV, respectively; P = 0.08). Patients with LSIL infected with high-risk HPV showed a higher rate of BLU methylation than those without HPV (38.8% vs 9.1%, respectively; P = 0.057). The methylation of RASSF1A was inversely related to HPV infection in patients with HSIL/SCC (P = 0.003). Conclusions: These results suggest that the methylation of BLU and RASSF1A genes is associated with cervical carcinogenesis, which could be clinically important in the future molecular screening of cervical neoplasia.