Esophageal squamous cell carcinoma (ESCC) has a very high incidence rate in northeastern Iran. Our team previously reported the BRCA2 p.K3326* mutation as a moderately penetrant ESCC susceptibility variant in northern Iran (OR = 3.64, 95% CI = 1.74-7.59, P = 0.0003). Recently, it has been reported that aldehydes can induce BRCA2 haploinsufficiency in cells with a heterozygous pathogenic BRCA2 mutation and predispose them to carcinogenic effects. Based on this observation, we speculate that ALDH2 dysfunctional variants may result in aldehyde-induced BRCA2 haploinsufficiency and increase cancer risk in BRCA2 carriers. In support of this hypothesis, our team recently reported the breast cancer risk modifying effect of an ALDH2 common polymorphism, rs10744777, among Polish carriers of the BRCA2 p.K3326* mutation.

In the current study, we assessed the interaction between the mentioned ALDH2 polymorphism and BRCA2 p.K3326* mutation in ESCC risk by genotyping the ALDH2 rs10744777 variant in the germline DNA of 746 ESCC cases and 1,373 controls from northern Iran who were previously genotyped for the BRCA2 p.K3326* mutation.

Among a total of 464 individuals with TT genotype of the ALDH2 rs10744777 polymorphism, which is associated with lower ALDH2 gene expression, we found 9 of 164 cases versus 3 of 300 controls who carried the BRCA2 p.K3326* variant (OR = 5.66, 95% CI = 1.22–26.2, P = 0.018).

Our finding supports our hypothesis that the ALDH2-rs10744777 TT genotype may be a significant risk modifier of ESCC in individuals with a BRCA2 p.K3326* mutation.