Introduction Menopausal hormone therapy (MHT) has been associated with reduced colorectal cancer (CRC) risk. Since the underlying biological mechanisms of MHT effects on CRC are unknown, we investigated whether single nucleotide polymorphisms (SNPs) in genes related to sex steroid metabolism, transport and signalling modify MHT-associated CRC risk.

Methods 47 SNPs in 16 candidate genes related to sex steroid transport (ABCB1), metabolism (COMT, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP17A1, GSTP, HSD17B1) and signalling (ESR1, ESR2, SHBG, PGR, NR1I2) were genotyped using genomic DNA samples from 685 female postmenopausal CRC patients and 684 controls without CRC of a German population-based case-control study (DACHS). Unconditional multivariate logistic regression was performed and effect modification was assessed using a multiplicative interaction term.

Results CRC risk associated with ever MHT use as well as with duration was significantly modified by rs1202168 in ABCB1 (p interaction =0.04). The MHT-associated risk reduction was no longer significant in homozygous non-carriers, while homozygous carriers of the minor T allele had a 57% lower risk with ever use of MHT and a 22% lower risk per 5 years of MHT use. Significant effect modification was also observed for rs910416 in ESR1, whereby the decreased CRC risk was attenuated in carriers of the minor C allele (p interaction =0.03 for ever use and 0.07 for duration of use).

Conclusion Our results provide the first evidence that polymorphisms in sex steroid-related genes may modify CRC risk associated with MHT. Our findings warrant replication in independent study populations.