Abstract
BackgroundHead-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.MethodsExtreme 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.ConclusionsAmong 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-016-0094-y) contains supplementary material, which is available to authorized users.
Highlights
Worldwide, head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common cancer
The purpose of this study was to search for single single-nucleotide polymorphism (SNP) marker and haplotype associations in these four selected genes that might be statistically significantly correlated with greater risk of Head-and-neck squamous cell carcinoma (HNSCC) in HS cancer patients, compared with HR heavy smokers having no cancer
We followed the clinical protocol—titled “Human Cancer and AHR/Name of enzyme (CYP1A1)/1A2/1B1 Gene Polymorphisms” (#03-08-07-01)—annually approved for the entire study, without any HIPAA issues or concerns, by the University of Cincinnati Medical Center Institutional Review Board (IRB)
Summary
Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common cancer. “cancer” represents a multifactorial trait involving hundreds, if not thousands, of genes, plus epigenetic and environmental effects. It remains possible, that—if a candidate-gene approach that embraces a method having sufficient statistical power is applied to a sufficiently large cohort— a genotype-phenotype association might be demonstrated for one or more “small-effect” genes. 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 tagSNPs) within and near these four genes [16 (AHR), 4 (CYP1A1), 4 (CYP1A2), and 12 (CYP1B1)] were chosen
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