Cyclin D1 promoter -56 and -54 bp CpG un-methylation predicts invasive progression in arsenic-induced Bowen's disease

Wei Ting Liao, Huey Ling You, Chee Yin Chai, Chih Hung Lee, Cheng Che E. Lan, Shun Jen Chang, Chu Ling Yu, Hsin Su Yu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

8 Scopus citations

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 -54 bp 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 -54 bp CpG in the CCND1 promoter serves as a predictor for invasive progression in As-BD patients.

Original languageEnglish
Pages (from-to)191-197
Number of pages7
JournalJournal of Dermatological Science
Volume89
Issue number2
DOIs
StatePublished - 02 2018

Bibliographical note

Publisher Copyright:
© 2017 Japanese Society for Investigative Dermatology

Keywords

  • Aneuploidy
  • Arsenic-induced Bowen's disease
  • Cyclin D1 un-methylation
  • Invasive progression
  • Predictor

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