Molecular characterization of DNA double strand breaks in cervical cancer

Abstract

Cervical cancer is the major cause of death in woman worldwide. Carcinogenesis show strong associated with HPV. DNA double strand breaks is another important caused of tumorigenesis. This study was to evaluate the potential of cyclin A1, which associated to DNA repairing mechanisms. We proposed cyclin A1 to act as a tumor suppressor gene in human papillomavirus-associated cervical cancer. Y. Tokumaru et al ., Cancer Res 64, 5982-7(Sep 1,2004) demonstrated in head and neck squamous-cell cancer an inverse correlation between cyclin A1 promoter hypermethylation and TP53 mutation. Human papillomavirus-associated cervical cancer, however, is deprived of TP53 mutation. Human papillomavirus-associated cervical cancer, however, is deprived of TP53 function by a different mechanism. Therefore, it was of interest to investigate the epigenetic alterations during multistep cervical cancer development. In this study, we performed duplex methylation-specific PCR and confirmed cyclin A1 methylation to be commonly found in cervical cancer, both in vitro and in vivo, with is physiological role being to decrease gene expression. More importantly, this study demonstrated that not only is cyclin A1 promoter hypermethylation strikingly common in cervical cancer, but is also specific to the invasive phenotype in comparison with other histopathological stages during multistep carcinogenesis. We investigated 43 samples of white blood cells, 25 normal cenvices, and 24, 5 and 30 human papillomavirus-associated premalignant, microinvasive and invasive cervical lesions, respectively. None of the normal cells and low-grade squamous intraepithelial lesions exhibited methylation. In contrast, 36.6%, 60% and 93.3% of high-grade squamous intraepithelial lesions, microinvasive and invasive cancers, respectively, showed methylation. Therefore, this methylation study indicated that cyclin A1 acts as a tumor suppressor gene and is a potential tumor marker for early diagnosis of invasive.