Association of ESR1 gene tagging SNPs with breast cancer risk.
Dunning AM., Healey CS., Baynes C., Maia A-T., Scollen S., Vega A., Rodríguez R., Barbosa-Morais NL., Ponder BAJ., SEARCH None., Low Y-L., Bingham S., EPIC None., Haiman CA., Le Marchand L., MEC None., Broeks A., Schmidt MK., ABCS None., Hopper J., Southey M., ABCFS None., Beckmann MW., Fasching PA., BBCC None., Peto J., Johnson N., BBCS None., Bojesen SE., Nordestgaard B., CGPS None., Milne RL., Benitez J., CNIO-BCS None., Hamann U., Ko Y., GENICA None., Schmutzler RK., Burwinkel B., GC-HBOC None., Schürmann P., Dörk T., HABCS None., Heikkinen T., Nevanlinna H., HEBCS None., Lindblom A., Margolin S., KARBAC None., Mannermaa A., Kosma V-M., KBCS None., Chen X., Spurdle A., kConFab and the AOCS Management Group None., Change-Claude J., Flesch-Janys D., MARIE None., Couch FJ., Olson JE., for MCBCS None., Severi G., Baglietto L., MCCS None., Børresen-Dale A-L., Kristensen V., NBCS None., Hunter DJ., Hankinson SE., NHS None., Devilee P., Vreeswijk M., ORIGO None., Lissowska J., Brinton L., PBCS None., Liu J., Hall P., SASBAC None., Kang D., Yoo K-Y., SEBCS None., Shen C-Y., Yu J-C., TWBCS None., Anton-Culver H., Ziogoas A., UCIBCS None., Sigurdson A., Struewing J., USRTS None., Easton DF., Garcia-Closas M., Humphreys MK., Morrison J., Pharoah PDP., Pooley KA., Chenevix-Trench G., BCAC None.
We have conducted a three-stage, comprehensive single nucleotide polymorphism (SNP)-tagging association study of ESR1 gene variants (SNPs) in more than 55,000 breast cancer cases and controls from studies within the Breast Cancer Association Consortium (BCAC). No large risks or highly significant associations were revealed. SNP rs3020314, tagging a region of ESR1 intron 4, is associated with an increase in breast cancer susceptibility with a dominant mode of action in European populations. Carriers of the c-allele have an odds ratio (OR) of 1.05 [95% Confidence Intervals (CI) 1.02-1.09] relative to t-allele homozygotes, P = 0.004. There is significant heterogeneity between studies, P = 0.002. The increased risk appears largely confined to oestrogen receptor-positive tumour risk. The region tagged by SNP rs3020314 contains sequence that is more highly conserved across mammalian species than the rest of intron 4, and it may subtly alter the ratio of two mRNA splice forms.