Multi-Variant Pathway Association Analysis Reveals the Importance of Genetic Determinants of Estrogen Metabolism in Breast and Endometrial Cancer Susceptibility

Abstract

Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML)–based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (p global = 0.034) and endometrial (p global = 0.052) cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (p global = 0.008) and endometrial cancer (p global = 0.014). The sub-pathway association was validated in the Finnish sample of breast cancer (p global = 0.015). Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (p global = 0.0003). Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite genetic determinants related to the androgen–estrogen conversion are important for the induction of two hormone-associated cancers, particularly for the hormone-driven breast tumour subtypes.

Genetic variation in the androgen estrogen conversion pathway in relation to breast cancer prognosticators

“…The SNPs/genes within the androgen-to-estrogen conversion pathway, which are included in the current study, represent a subset of SNPs/genes from a parent study of the entire estrogen metabolism pathway [4].…”

“…Numerous genetic association studies addressing association with cancer risk and genes in the estrogen metabolism pathway have been reported with conflicting results, probably reflecting the low penetrance of mutations in genes within the estrogen metabolism pathway, suboptimal study designs, underpowered studies or a combination of these factors [1][2][3]. We have recently been able to show, using a pathway approach, that there is an association between breast cancer risk and some of the genes involved in the androgen-to-estrogen conversion pathway (a sub-pathway of the complete estrogen metabolism pathway), particularly for the risk of estrogen receptor(ER)-positive tumours [4]. Gene-based analysis indicated that CYP19A1 was the major contributor to the observed association.…”

“…In the current study we investigated whether the top risk SNPs within the androgen-to-estrogen conversion sub-pathway, according to [4], are associated with breast cancer prognosticators; tumour grade, size and lymph node status. Prior to analysis we hypothesised that alleles associated with an increased risk of breast cancer are associated with good prognosis (and vice-versa) since hormone related breast cancers, identified in terms of menopausal hormone treatment have also been reported to be associated with favourable prognosis [7].…”

“…Controls were randomly chosen from the Swedish Registry of Total Population and frequency matched to cases, on age. Characteristics of the participants in the breast cancer case-control study have been described elsewhere [4,7,8]. For cancer patients, information on tumour characteristics was collected from patient records from surgical and oncological units throughout Sweden.…”

“…Written informed consent was obtained from all the participating subjects, and the study was approved by the Institutional Review Boards in Sweden and the National University of Singapore [4].…”