Genetic variants in CYP2B6 and HSD17B12 associated with the risk of squamous cell carcinoma of the head and neck
Menée à partir des données de 2 études américaines d'association à l'échelle du génome entier portant sur 4 493 témoins et 2 171 patients atteints d'un cancer de la tête et du cou, puis répliquée à l'aide de données européennes portant sur 6 034 patients et 6 585 témoins, cette étude identifie des polymorphismes à simple nucléotide de gènes impliqués dans le métabolisme des hydrocarbures aromatiques polycycliques et des nitrosamines spécifiques du tabac et associés au risque de développer la maladie
Polycyclic aromatic hydrocarbons (PAHs) and tobacco-specific nitrosamines (TSNA) metabolism-related genes play important role in the development of cancers. We assessed the associations of genetic variants in genes involved in the metabolism of PAHs and TSNA, and the risk of squamous cell carcinoma of the head and neck (SCCHN) in European populations using two published genome-wide association study datasets. In the single-locus analysis, we identified two SNPs (rs145533669 and rs35246205) in CYP2B6 to be associated with risk of SCCHN (P = 1.57 × 10−4 and 0.004), two SNPs (EPHX1 rs117522494 and CYP2B6 rs145533669) to be associated with risk of oropharyngeal cancer (P = 0.001 and 0.004), and one SNPs (rs4359199 in HSD17B12) to be associated with risk of oral cancer (P = 0.006). Significant interaction effect was found between rs4359199 and drinking status on risk of SCCHN and oropharyngeal cancer (P < 0.05). eQTL and sQTL analyzes revealed that two SNPs (CYP2B6 rs35246205 and HSD17B12 rs4359199) were correlated with alternative splicing or mRNA expression levels of the corresponding genes in liver cells (P < 0.05). In-silico functional annotation suggested that these two SNPs may regulate mRNA expression by affecting the binding of transcription factors. Results from phenome-wide association studies presented significant associations between these genes and risks of other cancers, smoking behavior, and alcohol dependence (P < 0.05). Our study provided insight into the underlying genetic mechanism of head and neck cancer and warranted future functional validation.