CYP19A1 fine-mapping and Mendelian randomization: Estradiol is causal for endometrial cancer

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

Research output: Contribution to journalArticleResearchpeer-review

30 Citations (Scopus)

Abstract

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancerandwith estradiol (E2) concentrations.We analyzed2937singlenucleotidepolymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome widesignificant 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 theobservedeffectonE2 concentrations (1.09, CI=1.03-1.21), consistentwith 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 associationswith rs727479 were stronger amongwomen with a higher BMI (PinteractionZ0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.

Original languageEnglish
Pages (from-to)77-91
Number of pages15
JournalEndocrine-Related Cancer
Volume23
Issue number2
DOIs
Publication statusPublished - 1 Feb 2016

Keywords

  • CYP19A1
  • Endometrial cancer
  • Estradiol

Cite this

Thompson, D. J., O'Mara, T. A., Glubb, D. M., Painter, J. N., Cheng, T., Folkerd, E., Doody, D., Dennis, J., Webb, P. M., Gorman, M., Martin, L., Hodgson, S., Michailidou, K., Tyrer, J. P., Maranian, M. J., Hall, P., Czene, K., Darabi, H., Li, J., ... Australian National Endometrial Cancer Study Group (ANECS) (2016). CYP19A1 fine-mapping and Mendelian randomization: Estradiol is causal for endometrial cancer. Endocrine-Related Cancer, 23(2), 77-91. https://doi.org/10.1530/ERC-15-0386