ESR1基因座的综合遗传评估确定了子宫内膜癌的一个风险区域。
Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer.
作者信息
O'Mara Tracy A, Glubb Dylan M, Painter Jodie N, Cheng Timothy, Dennis Joe, Attia John, Holliday Elizabeth G, McEvoy Mark, Scott Rodney J, Ashton Katie, Proietto Tony, Otton Geoffrey, Shah Mitul, Ahmed Shahana, Healey Catherine S, Gorman Maggie, Martin Lynn, Hodgson Shirley, Fasching Peter A, Hein Alexander, Beckmann Matthias W, Ekici Arif B, Hall Per, Czene Kamila, Darabi Hatef, Li Jingmei, Dürst Matthias, Runnebaum Ingo, Hillemanns Peter, Dörk Thilo, Lambrechts Diether, Depreeuw Jeroen, Annibali Daniela, Amant Frederic, Zhao Hui, Goode Ellen L, Dowdy Sean C, Fridley Brooke L, Winham Stacey J, Salvesen Helga B, Njølstad Tormund S, Trovik Jone, Werner Henrica M J, Tham Emma, Liu Tao, Mints Miriam, Bolla Manjeet K, Michailidou Kyriaki, Tyrer Jonathan P, Wang Qin, Hopper John L, Peto Julian, Swerdlow Anthony J, Burwinkel Barbara, Brenner Hermann, Meindl Alfons, Brauch Hiltrud, Lindblom Annika, Chang-Claude Jenny, Couch Fergus J, Giles Graham G, Kristensen Vessela N, Cox Angela, Pharoah Paul D P, Dunning Alison M, Tomlinson Ian, Easton Douglas F, Thompson Deborah J, Spurdle Amanda B
机构信息
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
出版信息
Endocr Relat Cancer. 2015 Oct;22(5):851-61. doi: 10.1530/ERC-15-0319.
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.
长期大量接触雌激素是子宫内膜癌（EC）公认的危险因素，尤其是对于子宫内膜样组织学类型的癌症。雌激素的生理功能主要由ESR1编码的雌激素受体α介导。因此，多项研究探讨了ESR1基因座的变异是否与EC风险相关，但结果相互矛盾。我们对6607例EC病例和37925例对照中的3633个基因分型和推算的单核苷酸多态性（SNP）进行了全面的精细定位分析。有证据表明，EC风险信号位于ESR1基因的一个潜在替代启动子处（主效SNP rs79575945，P=1.86×10⁻⁵），对于子宫内膜样亚型癌症更强（P=3.76×10⁻⁶）。生物信息学分析表明，该风险信号位于靶向ESR1的功能重要区域，eQTL分析发现rs79575945与邻近基因SYNE1的表达相关。总之，我们在全研究范围内确定了一个位于ESR1的单一EC风险信号。鉴于该基因座的SNP与乳腺癌风险相关，乳腺癌也是一种激素驱动的癌症，本研究为跨癌症类型进行知情候选精细尺度基因研究的理论依据提供了更多支持。
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