Common genetic variation in the sex hormone metabolic pathway and endometrial cancer risk: pathway-based evaluation of candidate genes

Abstract

Background: Estrogen plays a major role in endometrial carcinogenesis, suggesting that common variants of genes in the sex hormone metabolic pathway may be related to endometrial cancer risk. In support of this view, variants in CYP19A1 [cytochrome P450 (CYP), family 19, subfamily A, polypeptide 1] have been associated with both circulating estrogen levels and endometrial cancer risk. Associations with variants in other genes have been suggested, but findings have been inconsistent.

Methods: We examined 36 sex hormone-related genes using a tagging approach in a population-based case-control study of 417 endometrial cancer cases and 407 controls conducted in Poland. We evaluated common variation in these genes in relation to endometrial cancer risk using sequential haplotype scan, variable-sized sliding window and adaptive rank-truncated product (ARTP) methods.

Results: In our case-control study, the strongest association with endometrial cancer risk was for AR (androgen receptor; ARTP P = 0.006). Multilocus analyses also identified boundaries for a region of interest in AR and in CYP19A1 around a previously identified susceptibility loci. We did not find evidence for consistent associations between previously reported candidate single-nucleotide polymorphisms in this pathway and endometrial cancer risk.

Discussion: In summary, we identified regions in AR and CYP19A1 that are of interest for further evaluation in relation to endometrial cancer risk in future haplotype and subsequent fine mapping studies in larger study populations.

Fig. 1.

Description of the sex hormone metabolic pathway: genes involved in synthesis, bioactivation, metabolism, and inactivation of estrogen and other hormones.

Fig. 2.

AR and CYP19A1 sequential scan and variable-sized sliding window analyses in population-based case–control Polish Endometrial Cancer Study (417 cases and 407 controls).

Fig. 3.

Manhattan plot for 673 SNPs (excluded SNPs with minor allele frequency with <0.006) of 36 sex hormone-related genes examined in the population-based case–control Polish Endometrial Cancer Study (417 cases and 407 controls).