Abstract
Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10−11). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10−8). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11–1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03–1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
Highlights
Established risk factors for endometrial cancer include high BMI (IARC 2002), early menarche, late menopause, nulliparity, estrogen-only hormone replacement therapy (HRT) (Beral et al 2005) and tamoxifen use (Cuzick et al 2003), while cigarette smoking and the use of oral contraceptives or combined HRT (Beral et al 2005) are associated with lower risks
The association between single nucleotide polymorphisms (SNPs) at the CYP19A1 locus and endometrial cancer was tested using data from four separate case-control studies: The ANECS, SEARCH, and NSECG genomewide association studies The results presented here are based on the ANECS, SEARCH, and NSECG genomewide association studies (GWAS) and country-matched datasets (McGregor et al 1999, Wellcome Trust Case–Control Consortium (WTCCC) 2007, Houlston et al 2010, McEvoy et al 2010, Painter et al 2011, Spurdle et al 2011), as shown in Supplementary Table 1A and B, see section on supplementary data given at the end of this article, and described in detail in (Painter et al 2015)
The ECAC iCOGS study The fourth dataset comprised 4402 women of European ancestry with a confirmed diagnosis of endometrial cancer (3535 with confirmed endometrioid histology), recruited via 11 separate studies in seven countries in the Endometrial Cancer Association Consortium (ECAC; Painter et al 2015) and 28 758 healthy female controls from the same countries, all participating in the Breast Cancer Association Consortium (BCAC; Michailidou et al 2013) or the Ovarian Cancer Association Consortium (OCAC; Pharoah et al 2013), plus 282 Norwegian blood donor controls
Summary
Established risk factors for endometrial cancer include high BMI (IARC 2002), early menarche, late menopause, nulliparity, estrogen-only hormone replacement therapy (HRT) (Beral et al 2005) and tamoxifen use (Cuzick et al 2003), while cigarette smoking and the use of oral contraceptives or combined HRT (Beral et al 2005) are associated with lower risks. None of the published studies have attempted a systematic assessment of all common CYP19A1 variants in order to determine i) which are most likely to be causal for endometrial cancer and/or E2 concentration, ii) whether multiple independent causal variants exist at this locus for either trait, and iii) whether the same variant or variants are responsible for both traits The latter would help to address the question as to whether the reported association between E2 and endometrial cancer seen in epidemiological studies is causal or a consequence of confounding (Fig. 1). To address the question of whether the same CYP19A1 variant(s) are associated with E2 levels and endometrial cancer with compatible effect sizes and directions, we used genotype information for 2937 single nucleotide polymorphisms (SNPs) across a 1.2 Mb region encompassing CYP19A1 in 6608 endometrial cancer cases and 37 925 controls of European ancestry, 1733 of whom (all controls) were post-menopausal and had measured E2 and T concentrations. Individuals with !85% estimated European ancestry based on Identity-By-State (IBS) scores between study individuals and individuals in HapMap (http:// hapmap.ncbi.nlm.nih.gov/) were excluded
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