title: A population-based study of DNA repair gene variants in relation to non-melanoma skin cancer as a marker of a cancer-prone phenotype.
abstract: For unknown reasons, non-melanoma skin cancer (NMSC) is associated with increased risk of other malignancies. Focusing solely on DNA repair or DNA repair-related genes, this study tested the hypothesis that DNA repair gene variants contribute to the increased cancer risk associated with a personal history of NMSC. From the parent CLUE II cohort study, established in 1989 in Washington County, MD, the study consisted of a cancer-free control group (n 5 2296) compared with three mutually exclusive groups of cancer cases ascertained through 2007: (i) Other (non-NMSC) cancer only (n 5 2349); (ii) NMSC only (n 5 694) and (iii) NMSC plus other cancer (n 5 577). The frequency of minor alleles in 759 DNA repair gene single nucleotide polymorphisms (SNPs) was compared in these four groups. Comparing those with both NMSC and other cancer versus those with no cancer, 10 SNPs had allelic trend P-values <0.01. The two top-ranked SNPs were both within the thymine DNA glycosylase gene (TDG). One was a non-synonymous coding SNP (rs2888805) [per allele odds ratio (OR) 1.40, 95% confidence interval (CI) 1.16-1.70; P-value 5 0.0006] and the other was an intronic SNP in high linkage disequilibrium with rs2888805 (rs4135150). None of the associations had a P-value <6.6310(-5), the threshold for statistical significance after correcting for multiple comparisons. The results pinpoint DNA repair genes most likely to contribute to the NMSC cancer-prone phenotype. A promising lead is genetic variants in TDG, important not only in base excision repair but also in regulating the epigenome and gene expression, which may contribute to the NMSC-associated increase in overall cancer risk.
authors.affiliation: Department of Biostatistics, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Jorgensen
authors.forename: Yin Yao
authors.initials: YY
authors.lastname: Shugart
authors.forename: Yvette Berthier
authors.initials: YB
authors.lastname: Schaad
authors.forename: Bailey
authors.initials: B
authors.lastname: Kessing
authors.forename: Judith
authors.initials: J
authors.lastname: Hoffman-Bolton
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Helzlsouer
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Lee
authors.initials: L
authors.lastname: Wheless
authors.forename: Lesley
authors.initials: L
authors.lastname: Francis
authors.forename: Rhoda M
authors.initials: RM
authors.lastname: Alani
authors.forename: Paul T
authors.initials: PT
authors.lastname: Strickland
authors.forename: Michael W
authors.initials: MW
authors.lastname: Smith
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Alberg
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D004265:DNA Helicases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012878:Skin Neoplasms / Q000235:genetics*; D044502:Thymine DNA Glycosylase / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C072022:XPBC-ERCC-3 protein; D044502:Thymine DNA Glycosylase; D004265:DNA Helicases