Head-and-neck squamous cell carcinoma risk in smokers: no association detected between phenotype and AHR, CYP1A1, CYP1A2, or CYP1B1 genotype

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.

Lack of association between multiple polymorphisms in aryl hydrocarbon receptor (AhR) gene and cancer susceptibility

“…The previous studies found that the combination (multiple-variant haplotype) of multiple AhR polymorphisms contributed to the susceptibility of lung cancer [ 13 , 24 ]. Jorge-Nebert et al constructed multiple-variant haplotypes of AhR gene to investigate the association of theses haplotypes with head-and-neck squamous cell carcinoma, but no AhR haplotypes displayed statistically significant correlation with the risk of that cancer [ 36 ]. Haplotypic analysis which has bigger statistical power than single polymorphism analysis was carried out by some original studies, but it was impossible to perform the corresponding meta-analysis of AhR haplotypes attributing to inadequate haplotype data.…”

The Multifarious Link between Cytochrome P450s and Cancer

“…The substrate-inducible CYP1A1 and CYP1A2 are responsible for xenobiotic metabolism, such as polycyclic aromatic hydrocarbon metabolism [36][37][38][39][40]. In this group, charred food and cigarette smoke catalyze N-oxidation of carcinogenic aromatic and heterocyclic amines [41][42][43]. The enzymes are selective for planar molecules, which are carcinogens, as substrates.…”