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 Frederic,Goode Ellen L,Fridley Brooke L,Dowdy Sean C,Winham Stacey J,Salvesen Helga B,Trovik Jone,Njolstad Tormund S,Werner Henrica M J,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 D P,Dunning Alison M,Tomlinson Ian,Dowsett Mitch,Easton Douglas F,Spurdle Amanda B
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.
Subject
Cancer Research,Endocrinology,Oncology,Endocrinology, Diabetes and Metabolism