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Endocr Relat Cancer. 2015 Oct;22(5):851-61. doi: 10.1530/ERC-15-0319.

Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer.

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Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, Queensland 4006, Australia Wellcome Trust Centre for Human Genetics University of Oxford, Oxford OX3 7BN, UK Department of Public Health and Primary Care Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK Hunter Medical Research Institute John Hunter Hospital, Newcastle, New South Wales 2305, Australia School of Medicine and Public Health Centre for Clinical Epidemiology and Biostatistics, University of Newcastle, Newcastle, New South Wales 2305, Australia Hunter Area Pathology Service John Hunter Hospital, Newcastle, New South Wales 2305, Australia Centre for Information Based Medicine School of Biomedical Sciences and Pharmacy School of Medicine and Public Health University of Newcastle, Newcastle, New South Wales 2308, Australia Department of Oncology Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK Department of Clinical Genetics St George's, University of London, London SW17 0RE, UK Division of Hematology/Oncology Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA Department of Gynecology and Obstetrics University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen 91054, Germany Institute of Human Genetics University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, Germany Department of Medical Epidemiology and Biostatistics Karolinska Institutet, Stockholm SE-171 77, Sweden Department of Gynaecology Jena University Hospital - Friedrich Schiller University, Jena 07743, Germany Hannover Medical School Clinics of Gynaecology and Obstetrics, Hannover 30625, Germany Gynaecology Research Unit Hannover Medical School, Hannover 30625, Germany Vesalius Research Center Leuven 3000, Belgium Laboratory for Translational Genetics


Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.


ESR1; endometrial cancer; fine-mapping analysis; single-nucleotide polymorphisms

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