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Endocrine-related Cancer

Publication date: 2016-02-01
Volume: 23 Pages: 77 - 91
Publisher: Published for the Society of Endocrinology by the Journal of Endocrinology Ltd.

Author:

Thompson, Deborah J
O'Mara, Tracy A ; Glubb, Dylan M ; Painter, Jodie N ; Cheng, Timothy ; Folkerd, Elizabeth ; Doody, Deborah ; Dennis, Joe ; Webb, Penelope M ; Gorman, Maggie ; Martin, Lynn ; Hodgson, Shirley ; Michailidou, Kyriaki ; Tyrer, Jonathan P ; Maranian, Mel J ; Hall, Per ; Czene, Kamila ; Darabi, Hatef ; Li, Jingmei ; Fasching, Peter A ; Hein, Alexander ; Beckmann, Matthias W ; Ekici, Arif B ; Dörk, Thilo ; Hillemanns, Peter ; Dürst, Matthias ; Runnebaum, Ingo ; Zhao, Hui ; Depreeuw, Jeroen ; Schrauwen, Stefanie ; Amant, Frédéric ; Goode, Ellen L ; Fridley, Brooke L ; Dowdy, Sean C ; Winham, Stacey J ; Salvesen, Helga B ; Trovik, Jone ; Njolstad, Tormund S ; Werner, Henrica MJ ; Ashton, Katie ; Proietto, Tony ; Otton, Geoffrey ; Carvajal-Carmona, Luis ; Tham, Emma ; Liu, Tao ; Mints, Miriam ; Scott, Rodney J ; McEvoy, Mark ; Attia, John ; Holliday, Elizabeth G ; Montgomery, Grant W ; Martin, Nicholas G ; Nyholt, Dale R ; Henders, Anjali K ; Hopper, John L ; Traficante, Nadia ; Ruebner, Matthias ; Swerdlow, Anthony J ; Burwinkel, Barbara ; Brenner, Hermann ; Meindl, Alfons ; Brauch, Hiltrud ; Lindblom, Annika ; Lambrechts, Diether ; Chang-Claude, Jenny ; Couch, Fergus J ; Giles, Graham G ; Kristensen, Vessela N ; Cox, Angela ; Bolla, Manjeet K ; Wang, Qin ; Bojesen, Stig E ; Shah, Mitul ; Luben, Robert ; Khaw, Kay-Tee ; Pharoah, Paul DP ; Dunning, Alison M ; Tomlinson, Ian ; Dowsett, Mitch ; Easton, Douglas F ; Spurdle, Amanda B

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Endocrinology & Metabolism, endometrial cancer, CYP19A1, estradiol, GENOME-WIDE ASSOCIATION, CORONARY-HEART-DISEASE, SEX STEROID-HORMONES, BREAST-CANCER, POSTMENOPAUSAL WOMEN, SUSCEPTIBILITY LOCI, COHORT CONSORTIUM, GENETIC-VARIATION, ESTROGEN-LEVELS, RISK-FACTORS, Age Factors, Alleles, Aromatase, Body Mass Index, Case-Control Studies, Endometrial Neoplasms, Estradiol, Female, Gene-Environment Interaction, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Phenotype, Polymorphism, Single Nucleotide, Australian National Endometrial Cancer Study Group (ANECS), National Study of Endometrial Cancer Genetics Group (NSECG), for RENDOCAS, AOCS Group, 06 Biological Sciences, 11 Medical and Health Sciences, Oncology & Carcinogenesis, 3202 Clinical sciences, 3211 Oncology and carcinogenesis

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.