Polymorphism in xenobiotic and estrogen metabolizing genes, exposure to perfluorinated compounds and subsequent breast cancer risk: A nested case-control study in the Danish National Birth Cohort

In the present case-cohort study based on prospective data from Danish women, we aimed to estimate the main effect of polymorphisms in genes known to be involved in the steroid hormone metabolic pathway and xenobiotic metabolism on the risk of developing breast cancer. We also studied a possible effect measure modification between genotypes and levels of serum perfluoroalkylated substances (PFASs) on the risk to breast cancer. We have previously reported a weak association between serum PFASs levels and the risk of breast cancer for this study population of Danish pregnant nulliparous women as well as in a smaller case-control study of Greenlandic women. The study population consisted of 178 breast cancer cases and 233 controls (tabnulliparous and frequency matched on age) nested within the Danish National Birth Cohort (DNBC), which was established in 1996-2002. Blood samples were drawn at the time of enrollment (6-14 week of gestation). Serum levels of 10 perfluorocarboxylated acids (PFCAs), 5 perfluorosulfonated acids (PFSAs) and 1 sulfonamide (perflurooctane-sulfonamide, PFOSA) were measured. Genotyping was conducted for CYPIA1 (Ile462Val; rs1048943), CYP1B1 (Leu432Val; rs1056836), COMT (Va1158Met; rs4680), CYP17A1 (A1 -> A2; rs743572); CYPI9A1 (C -> T; rs10046) by the TaqMan allelic discrimination method. In overall, no significant associations were found between the investigated polymorphisms and the risk of breast cancer in this study among Danish women. The previously found association between PFOSA and risk of breast cancer did vary between different genotypes, with significantly increased risk confined to homozygous carriers of the following alleles: COMT (Met), CYP17 (A1) and CYP19 (C). Conclusion:Our results indicate that polymorphisms in COMT, CYP17 and CYP19 which are involved in estrogen biosynthesis and metabolism can modulate the potential effects of PFOSA exposure on the development of breast cancer.