Exome-wide analyses identify low-frequency variant in CYP26B1 and additional coding variants associated with esophageal squamous cell carcinoma
A partir de données portant sur 3 714 patients atteints d'un carcinome épidermoïde de l'œsophage et sur 3 880 témoins, puis répliquée sur des échantillons prélevés sur 7 002 patients et 8 757 témoins, cette étude sur l'exome entier identifie 6 nouveaux loci de susceptibilité et 3 variants de faible fréquence allélique impliqués dans l'étiologie de la maladie
Genome-wide association studies have identified common variants associated with risk of esophageal squamous cell carcinoma (ESCC). However, these common variants cannot explain all heritability of ESCC. Here we report an exome-wide interrogation of 3,714 individuals with ESCC and 3,880 controls for low-frequency susceptibility loci, with two independent replication samples comprising 7,002 cases and 8,757 controls. We found six new susceptibility loci in CCHCR1, TCN2, TNXB, LTA, CYP26B1 and FASN (P = 7.77 × 10−24 to P = 1.49 × 10−11), and three low-frequency variants had relatively high effect size (odds ratio > 1.5). Individuals with the rs138478634-GA genotype had significantly lower levels of serum all-trans retinoic acid, an anticancer nutrient, than those with the rs138478634-GG genotype (P = 0.0004), most likely due to an enhanced capacity of variant CYP26B1 to catabolize this agent. These findings emphasize the important role of rare coding variants in the development of ESCC.
Nature Genetics 2018