Hypermethylation and loss of heterozygosity of tumor suppressor genes on chromosome 3p in cervical cancer

We examined the promoter methylation status and LOH of the chromosome 3p genes, von Hippel-Lindau disease (VHL), retinoic acid receptor β (RAR-β), RAS association domain family 1A (RASSF1A), and fragile histidine triad (FHIT), in 37 samples of cervical squamous cell carcinoma and corresponding noncancerous tissues. We also analyzed the expression of RAR-β protein by immunohistochemistry. Promoter hypermethylation in RAR-β and FHIT was detected in 41% and 24% of tumors, respectively, whereas, no hypermethylation was detected in the corresponding noncancerous tissues. LOH in the regions of VHL, RAR-β, RASSF1A, and FHIT was observed in 3%, 30%, 22%, and 10% of informative cases, respectively. There were no correlations between LOH and promoter hypermethylation for all of these genes. Absent immunostaining of RAR-β protein correlated with hypermethylation and/or LOH of RAR-β gene. In addition, it correlated with higher level of SCC antigen and more frequent lymph node metastasis. Although biallelic inactivation by hypermethylation and concomitant LOH was infrequent, the high frequency of promoter hypermethylation and/or LOH of RAR-β and FHIT suggest that they play a role in cervical carcinogenesis independently. In addition, expression of RAR-β protein might be used as a prognostic factor in this disease.