Wei-Ting Liao1, Huey-Ling You2, Chee-Yin Chai3, Chih-Hung Lee4, Cheng-Che E Lan5, Shun-Jen Chang6, Chu-Ling Yu7, Hsin-Su Yu8. 1. Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan(c)Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. 2. Departments of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital, Taiwan. 3. Department of Pathology, Kaohsiung Medical University and Hospital, Kaohsiung, Taiwan. 4. Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. 5. Department of Dermatology, Kaohsiung Medical University and Hospital, Kaohsiung, Taiwan. 6. Department of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, Taiwan. 7. Taipei Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan. 8. Department of Dermatology, Kaohsiung Medical University and Hospital, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, Kaohsiung Medical University and Hospital, Kaohsiung, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Taiwan. Electronic address: yup.kmu@gmail.com.
Abstract
BACKGROUND: Patients with arsenic-induced Bowen's disease (As-BD) are at risk of developing invasive cancers in the skin, lung, and urinary bladder. However, a longitudinal follow-up study on the association between As-BD and invasive cancers is still lacking. OBJECTIVES: This study aims to investigate the underlying molecular mechanisms of this malignant progression in the skin and internal organs. METHODS: This is a biopsy-based follow-up study. We tested the DNA histograms, Cyclin D1 (CCND1) protein expression and CCND1 promoter DNA methylation in 40 pathologically confirmed specimens from As-BD patients to correlate with individual's invasive cancer occurrence in the 5-year follow-up. RESULTS: Flow cytometric DNA histogram analysis of skin specimens showed aneuploid (n=15), G2/M arrest (n=22), and normal (n=3) DNA histograms. No patients with normal DNA histograms developed invasive cancers, whereas 13 developed invasive cancers in the aneuploid group and 2 developed invasive cancers in the G2/M arrest group. The aneuploid group showed a high risk of invasive cancer development. In all assessed aneuploid specimens, the CCND1 promoter hypomethylation was observed. Statistically, percentage of un-methylation more than 55.85% among 17 detected CpG sites showed extremely high predictive power in the occurrence of invasive arsenical cancers. Furthermore, the un-methylation at -56 and -54bp CpG sites was statistically significantly associated with invasive arsenical cancer development (p=1.29×10-5). CONCLUSIONS: As-BD lesions showing an aneuploid DNA histogram had a high risk of invasive cancer development. Un-methyaltion at -56 and -54bp CpG in the CCND1 promoter serves as a predictor for invasive progression in As-BD patients.
BACKGROUND:Patients with arsenic-induced Bowen's disease (As-BD) are at risk of developing invasive cancers in the skin, lung, and urinary bladder. However, a longitudinal follow-up study on the association between As-BD and invasive cancers is still lacking. OBJECTIVES: This study aims to investigate the underlying molecular mechanisms of this malignant progression in the skin and internal organs. METHODS: This is a biopsy-based follow-up study. We tested the DNA histograms, Cyclin D1 (CCND1) protein expression and CCND1 promoter DNA methylation in 40 pathologically confirmed specimens from As-BD patients to correlate with individual's invasive cancer occurrence in the 5-year follow-up. RESULTS: Flow cytometric DNA histogram analysis of skin specimens showed aneuploid (n=15), G2/M arrest (n=22), and normal (n=3) DNA histograms. No patients with normal DNA histograms developed invasive cancers, whereas 13 developed invasive cancers in the aneuploid group and 2 developed invasive cancers in the G2/M arrest group. The aneuploid group showed a high risk of invasive cancer development. In all assessed aneuploid specimens, the CCND1 promoter hypomethylation was observed. Statistically, percentage of un-methylation more than 55.85% among 17 detected CpG sites showed extremely high predictive power in the occurrence of invasive arsenical cancers. Furthermore, the un-methylation at -56 and -54bp CpG sites was statistically significantly associated with invasive arsenical cancer development (p=1.29×10-5). CONCLUSIONS: As-BD lesions showing an aneuploid DNA histogram had a high risk of invasive cancer development. Un-methyaltion at -56 and -54bp CpG in the CCND1 promoter serves as a predictor for invasive progression in As-BD patients.