title: Head-and-neck squamous cell carcinoma risk in smokers: no association detected between phenotype and AHR, CYP1A1, CYP1A2, or CYP1B1 genotype.
abstract: Head-and-neck squamous cell carcinoma (HNSCC) differs between smokers and nonsmokers in etiology and clinical presentation. Because of demonstrated unequivocal involvement in smoking-induced cancer in laboratory animals, four candidate genes--AHR, CYP1A1, CYP1A2, and CYP1B1--were selected for a clinical genotype-phenotype association study of HNSCC risk in smokers. Thirty-six single-nucleotide variants (mostly tag-SNPs) within and near these four genes [16 (AHR), 4 (CYP1A1), 4 (CYP1A2), and 12 (CYP1B1)] were chosen.
  
  
  
  Extreme discordant phenotype (EDP) method of analysis was used to increase statistical power. HNSCC patients--having smoked 1-40 cigarette pack-years--represented the "highly-sensitive" (HS) population; heavy smokers having smoked ≥80 cigarette-pack-years without any type of cancer comprised the "highly-resistant" (HR) group. The vast majority of smokers were intermediate and discarded from consideration. Statistical tests were performed on N = 112 HS and N = 99 HR DNA samples from whole blood.
  
  
  
  Among the four genes and flanking regions--one haploblock, ACTTGATC in the 5' portion of CYP1B1, retained statistical significance after 100,000 permutations (P = 0.0042); among our study population, this haploblock was found in 36.4% of African-American, but only 1.49% of Caucasian, HNSCC chromosomes. Interestingly, in the 1000 Genomes Project database, frequency of this haplotype (in 1322 African and 1006 Caucasian chromosomes) is 0.356 and 0.003, respectively. This study represents an excellent example of "spurious association by population stratification". Considering the cohort size, we therefore conclude that the variant alleles chosen for these four genes, alone or in combinations, are not statistically significantly associated with risk of cigarette-smoking-induced HNSCC.
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267-0056, USA.
authors.forename: Lucia F
authors.initials: LF
authors.lastname: Jorge-Nebert
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267-0056, USA.|Division of Human Genetics, Department of Pediatrics & Molecular Developmental Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, 45229-2899, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0528, USA.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Wilson
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267-0056, USA.|Present address: Genesky Diagnostics, Suzhou, China.
authors.forename: Zhengwen
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0533, USA.
authors.forename: Randall
authors.initials: R
authors.lastname: Butler
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0528, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Gluckman
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267-0056, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Pinney
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267-0056, USA. dan.nebert@uc.edu.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C569463:CYP1A1 protein, human; C504573:CYP1A2 protein, human; C585496:CYP1B1 protein, human
keywords: AHR gene; CYP1A1; CYP1A2; CYP1B1 genes; Candidate-gene approach to genotype-phenotype association; Cigarette smoking; Extreme discordant phenotype method; Head-and-neck squamous cell carcinoma (HNSCC); Population stratification; Tag-SNPs (single nucleotide polymorphisms)