Hypermethylation of two consecutive tumor suppressor genes, BLU and RASSF1A, located at 3p21.3 in cervical neoplasias.
OBJECTIVE
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.
Lai
Hung-Cheng
HC
Department of Obstetrics and Gynecology, Tri-Service General Hospital, Taipei, Taiwan, ROC.
Lin
Ya-Wen
YW
Chang
Cheng-Chang
CC
Wang
Hui-Chen
HC
Chu
Ta-Wei
TW
Yu
Mu-Hsien
MH
Chu
Tang-Yuan
TY
D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3; D003598:Cytoskeletal Proteins; D019175:DNA Methylation; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics / Q000821:virology; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000821:virology
D003598:Cytoskeletal Proteins; D004279:DNA, Viral; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; C472720:ZMYND10 protein, human