title: Haplotypes of DNMT1 and DNMT3B are associated with mutagen sensitivity induced by benzo[a]pyrene diol epoxide among smokers.
abstract: The mutagen sensitivity assay is an in vitro measure of DNA repair capacity used to evaluate intrinsic susceptibility for cancer. The high heritability of mutagen sensitivity to different mutagens validates the use of this phenotype to predict cancer susceptibility. However, genetic determinants of mutagen sensitivity have not been fully characterized. Recently, several studies found that three major cytosine DNA methyltransferases (DNMTs), especially DNMT1, have a direct role in the DNA damage response, independent of their methyltransferase activity. This study evaluated the hypothesis that sequence variants in DNMT1, DNMT3A and DNMT3B are associated with mutagen sensitivity induced by the tobacco carcinogen benzo[a]pyrene diol epoxide (BPDE) in 278 cancer-free smokers. Single-nucleotide polymorphisms (n = 134) dispersed over the entire gene and regulatory regions of these DNMTs were genotyped by the Illumina Golden Gate Assay. DNA sequence variation in the DNMT1 and DNMT3B loci was globally associated with breaks per cell (P < 0.04 for both). No global association between DNMT3A and breaks per cell was seen (P = 0.09). Two haplotypes in block1 of DNMT1 (H284) and 3B (H70) were associated with 16 and 24% increase in breaks per cell, respectively. Subjects with three or four adverse haplotypes of both DNMT1 and 3B had a 50% elevation in mean level of breaks per cell compared with persons without adverse alleles (P = 0.004). The association between sequence variants of DNMT1 and 3B and mutagen sensitivity induced by BPDE supports the involvement of these DNMTs in protecting the cell from DNA damage.
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive Southeast, Albuquerque, NM 87108, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Leng
authors.forename: Christine A
authors.initials: CA
authors.lastname: Stidley
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Bernauer
authors.forename: Maria A
authors.initials: MA
authors.lastname: Picchi
authors.forename: Xin
authors.initials: X
authors.lastname: Sheng
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Frasco
authors.forename: David
authors.initials: D
authors.lastname: Van Den Berg
authors.forename: Frank D
authors.initials: FD
authors.lastname: Gilliland
authors.forename: Richard E
authors.initials: RE
authors.lastname: Crowell
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D000328:Adult; D000368:Aged; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009152:Mutagenicity Tests; D009153:Mutagens; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D009153:Mutagens; D000097584:DNA Methyltransferase 3B; C000619380:DNMT1 protein, human