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

Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer. O'Mara, T. A., Glubb, D. M., Painter, J. N., Cheng, T., Dennis, J., Australian National Endometrial Cancer Study Group (ANECS), Attia, J., Holliday, E. G., McEvoy, M., Scott, R. J., Ashton, K., Proietto, T., Otton, G., Shah, M., Ahmed, S., Healey, C. S., Gorman, M., Martin, L., National Study of Endometrial Cancer Genetics Group (NSECG), Hodgson, S., Fasching, P. A., Hein, A., Beckmann, M. W., Ekici, A. B., Hall, P., Czene, K., Darabi, H., Li, J., Dürst, M., Runnebaum, I., Hillemanns, P., Dörk, T., Lambrechts, D., Depreeuw, J., Annibali, D., Amant, F., Zhao, H., Goode, E. L., Dowdy, S. C., Fridley, B. L., Winham, S. J., Salvesen, H. B., Njølstad, T. S., Trovik, J., Werner, H. M. J., Tham, E., Liu, T., Mints, M., RENDOCAS, Bolla, M. K., Michailidou, K., Tyrer, J. P., Wang, Q., Hopper, J. L., AOCS Group, Peto, J., Swerdlow, A. J., Burwinkel, B., Brenner, H., Meindl, A., Brauch, H., Lindblom, A., Chang-Claude, J., Couch, F. J., Giles, G. G., Kristensen, V. N., Cox, A., Pharoah, P. D. P., Dunning, A. M., Tomlinson, I., Easton, D. F., Thompson, D. J., & Spurdle, A. B. Endocrine-Related Cancer, 22(5):851–861, October, 2015.
doi abstract bibtex

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.

@article{omara_comprehensive_2015,
	title = {Comprehensive genetic assessment of the {ESR1} locus identifies a risk region for endometrial cancer},
	volume = {22},
	issn = {1479-6821},
	doi = {10.1530/ERC-15-0319},
	abstract = {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.},
	language = {eng},
	number = {5},
	journal = {Endocrine-Related Cancer},
	author = {O'Mara, Tracy A. and Glubb, Dylan M. and Painter, Jodie N. and Cheng, Timothy and Dennis, Joe and {Australian National Endometrial Cancer Study Group (ANECS)} and Attia, John and Holliday, Elizabeth G. and McEvoy, Mark and Scott, Rodney J. and Ashton, Katie and Proietto, Tony and Otton, Geoffrey and Shah, Mitul and Ahmed, Shahana and Healey, Catherine S. and Gorman, Maggie and Martin, Lynn and {National Study of Endometrial Cancer Genetics Group (NSECG)} and Hodgson, Shirley and Fasching, Peter A. and Hein, Alexander and Beckmann, Matthias W. and Ekici, Arif B. and Hall, Per and Czene, Kamila and Darabi, Hatef and Li, Jingmei and Dürst, Matthias and Runnebaum, Ingo and Hillemanns, Peter and Dörk, Thilo and Lambrechts, Diether and Depreeuw, Jeroen and Annibali, Daniela and Amant, Frederic and Zhao, Hui and Goode, Ellen L. and Dowdy, Sean C. and Fridley, Brooke L. and Winham, Stacey J. and Salvesen, Helga B. and Njølstad, Tormund S. and Trovik, Jone and Werner, Henrica M. J. and Tham, Emma and Liu, Tao and Mints, Miriam and {RENDOCAS} and Bolla, Manjeet K. and Michailidou, Kyriaki and Tyrer, Jonathan P. and Wang, Qin and Hopper, John L. and {AOCS Group} and Peto, Julian and Swerdlow, Anthony J. and Burwinkel, Barbara and Brenner, Hermann and Meindl, Alfons and Brauch, Hiltrud and Lindblom, Annika and Chang-Claude, Jenny and Couch, Fergus J. and Giles, Graham G. and Kristensen, Vessela N. and Cox, Angela and Pharoah, Paul D. P. and Dunning, Alison M. and Tomlinson, Ian and Easton, Douglas F. and Thompson, Deborah J. and Spurdle, Amanda B.},
	month = oct,
	year = {2015},
	pmid = {26330482},
	pmcid = {PMC4559752},
	keywords = {Breast Neoplasms, Case-Control Studies, Computational Biology, Cytoskeletal Proteins, Databases, Genetic, ESR1, Endometrial Neoplasms, Estrogen Receptor alpha, Female, Genetic Loci, Genetic Predisposition to Disease, Genotype, Humans, Meta-Analysis as Topic, Nerve Tissue Proteins, Nuclear Proteins, Polymorphism, Single Nucleotide, Prognosis, Promoter Regions, Genetic, Risk Factors, endometrial cancer, fine-mapping analysis, single-nucleotide polymorphisms},
	pages = {851--861},
}

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