Lai Hung-Cheng, Lin Ya-Wen, Chang Cheng-Chang, Wang Hui-Chen, Chu Ta-Wei, Yu Mu-Hsien, Chu Tang-Yuan
Department of Obstetrics and Gynecology, Tri-Service General Hospital, Taipei, Taiwan, ROC.
Gynecol Oncol. 2007 Mar;104(3):629-35. doi: 10.1016/j.ygyno.2006.10.003. Epub 2006 Nov 13.
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.
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.
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).
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.
尽管宫颈癌发生由人乳头瘤病毒（HPV）引发，但还需要其他辅助因素来决定其自然发展进程。诸如DNA甲基化等表观遗传效应被认为与致癌过程有关。
对一系列宫颈肿瘤组织，包括45例低级别鳞状上皮内瘤变（LSIL）、63例高级别鳞状上皮内瘤变（HSIL）、107例鳞状细胞癌（SCC）、23例腺癌（AC）以及44例正常对照组织，评估BLU和RASSF1A的甲基化状态以及HPV感染状态。
SCC中76.9%、HSIL中57.4%、LSIL中20.0%以及正常组织中12.5%检测到BLU甲基化（P<0.001）。SCC中15%、HSIL中17.5%检测到RASSF1A甲基化，而LSIL和正常组织中未检测到（P<0.001）。在AC中，43.5%的患者检测到BLU甲基化，26.1%检测到RASSF1A甲基化，显著高于相应对照频率的12.5%（P=0.005）和0%（P=0.001）。随着SCC临床分期的进展，BLU甲基化有不显著的降低趋势（I期、II期和III/IV期分别为84.8%、67.7%和63.6%；P=0.08）。感染高危HPV的LSIL患者中BLU甲基化率高于未感染HPV的患者（分别为38.8%和9.1%；P=0.057）。在HSIL/SCC患者中，RASSF1A甲基化与HPV感染呈负相关（P=0.003）。
这些结果表明，BLU和RASSF1A基因的甲基化与宫颈癌发生有关，这在未来宫颈癌的分子筛查中可能具有重要临床意义。
