title: Aberrant methylation of hypermethylated-in-cancer-1 and exocyclic DNA adducts in tobacco smokers.
abstract: Tobacco smoke has been shown to produce both DNA damage and epigenetic alterations. However, the potential role of DNA damage in generating epigenetic changes is largely underinvestigated in human studies. We examined the effects of smoking on the levels of DNA methylation in genes for tumor protein p53, cyclin-dependent kinase inhibitor2A, hypermethylated-in-cancer-1 (HIC1), interleukin-6, Long Interspersed Nuclear Element type1, and Alu retrotransposons in blood of 177 residents in Thailand using bisulfite-PCR andpyrosequencing. Then, we analyzed the relationship of this methylation with the oxidative DNA adduct, M₁dG (a malondialdehyde adduct), measured by ³²P-postlabeling. Multivariate statistical analyses showed that HIC1 methylation levels were significantly increased in smokers compared with nonsmokers (p ≤ .05). A dose response was observed, with the highest HIC1 methylation levels in smokers of ≥ 10 cigarettes/day relative to nonsmokers and intermediate values in smokers of 1-9 cigarettes/day (p for trend ≤ .001). No additional relationships were observed. We also evaluated correlations between M₁dG and the methylation changes at each HIC1 CpG site individually. The levels of this adduct in smokers showed a significant linear correlation with methylation at one of the 3 CpGs evaluated in HIC1: hypermethylation at position 1904864340 was significantly correlated with the adduct M₁dG (covariate-adjusted regression coefficient (β) = .224 ± .101 [SE], p ≤ .05). No other correlations were detected. Our study extends prior work by others associating hypermethylation of HIC1 with smoking; shows that a very specific hypermethylation event can arise from smoking; and encourages future studies that explore a possible role for M₁dG in connecting smoking to this latter hypermethylation.
authors.affiliation: * Cancer Risk Factor Branch, Cancer Prevention and Research Institute, Florence, Italy;
authors.forename: Marco E M
authors.initials: ME
authors.lastname: Peluso
authors.forename: Armelle
authors.initials: A
authors.lastname: Munnia
authors.forename: Valentina
authors.initials: V
authors.lastname: Bollati
authors.forename: Petcharin
authors.initials: P
authors.lastname: Srivatanakul
authors.forename: Adisorn
authors.initials: A
authors.lastname: Jedpiyawongse
authors.forename: Suleeporn
authors.initials: S
authors.lastname: Sangrajrang
authors.forename: Marcello
authors.initials: M
authors.lastname: Ceppi
authors.forename: Roger W
authors.initials: RW
authors.lastname: Giese
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Baccarelli
mesh_terms: D000328:Adult; D018899:CpG Islands / Q000187:drug effects; D018736:DNA Adducts / Q000032:analysis*; D019175:DNA Methylation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D016014:Linear Models; D008297:Male; D008315:Malondialdehyde / Q000032:analysis*; D008875:Middle Aged; D015999:Multivariate Analysis; D012307:Risk Factors; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics* / Q000378:metabolism; D016540:Smoking Cessation; D000074606:Smoking Prevention; D013785:Thailand
chemical_list: D018736:DNA Adducts; C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D012906:Smoke; D008315:Malondialdehyde
keywords: HIC1; M1dG.; overall and site specific methylation; oxidative DNA damage; tobacco smoking