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. 2009 Mar 15;18(6):1131-9.
doi: 10.1093/hmg/ddn429. Epub 2009 Jan 6.

Association of ESR1 gene tagging SNPs with breast cancer risk

Alison M Dunning  1 , Catherine S Healey, Caroline Baynes, Ana-Teresa Maia, Serena Scollen, Ana Vega, Raquel Rodríguez, Nuno L Barbosa-Morais, Bruce A J Ponder; SEARCH; Yen-Ling Low, Sheila Bingham; EPIC; Christopher A Haiman, Loic Le Marchand; MEC; Annegien Broeks, Marjanka K Schmidt; ABCS; John Hopper, Melissa Southey; ABCFS; Matthias W Beckmann, Peter A Fasching; BBCC; Julian Peto, Nichola Johnson; BBCS; Stig E Bojesen, Børge Nordestgaard; CGPS; Roger L Milne, Javier Benitez; CNIO-BCS; Ute Hamann, Yon Ko; GENICA; Rita K Schmutzler, Barbara Burwinkel; GC-HBOC; Peter Schürmann, Thilo Dörk; HABCS; Tuomas Heikkinen, Heli Nevanlinna; HEBCS; Annika Lindblom, Sara Margolin; KARBAC; Arto Mannermaa, Veli-Matti Kosma; KBCS; Xiaoqing Chen, Amanda Spurdle; kConFab and the AOCS Management Group; Jenny Change-Claude, Dieter Flesch-Janys; MARIE; Fergus J Couch, Janet E Olson; for MCBCS; Gianluca Severi, Laura Baglietto; MCCS; Anne-Lise Børresen-Dale, Vessela Kristensen; NBCS; David J Hunter, Susan E Hankinson; NHS; Peter Devilee, Maaike Vreeswijk; ORIGO; Jolanta Lissowska, Louise Brinton; PBCS; Jianjun Liu, Per Hall; SASBAC; Daehee Kang, Keun-Young Yoo; SEBCS; Chen-Yang Shen, Jyh-Cherng Yu; TWBCS; Hoda Anton-Culver, Argyrios Ziogoas; UCIBCS; Alice Sigurdson, Jeff Struewing; USRTS; Douglas F Easton, Montserrat Garcia-Closas, Manjeet K Humphreys, Jonathan Morrison, Paul D P Pharoah, Karen A Pooley, Georgia Chenevix-Trench; BCAC
Affiliations

Association of ESR1 gene tagging SNPs with breast cancer risk

Alison M Dunning et al. Hum Mol Genet. .

Abstract

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.

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Figures

Figure 1.
Figure 1.
Haploview output. The matrix indicates the correlation coefficient between each pair of SNPs (RP2)—darker colours are equivalent to higher values. The relative positions of the ESR1 exons and haplotype blocks are shown together with the region of intron 4 tagged by SNP rs3020314.
Figure 2.
Figure 2.
Forrest plots. Results from meta-analysis of SNP rs3020314, using a dominant model, in (A) 21 invasive breast cancer case control studies from Europe and (B) 2 studies from Asia. (C) The subset of 17 studies (all European) with recorded ER+ tumours.
Figure 3.
Figure 3.
Ratios of RNA isoforms by genotype. (A) Plots showing ratios of Δ5ERα(Delta5) to full-length (FL) RNA, determined by gel fluorescence intensity in B-lymphocytes from 33 subjects who had also been genotyped for SNP rs3021314. Genotypes and number of subjects (n) in each class are shown beneath each plot, horizontal bars indicate mean values. (B) Plots showing relative amounts of Delta5 to FL RNA, determined by real-time PCR, in 30 ER+ breast tumours from subjects whose germline DNA had been genotyped for SNP rs3021314. Genotypes and number of subjects (n) in each class are shown beneath each box, and horizontal bars indicate mean values. Relative amounts are shown as the difference in PCR cycle number needed to reach a given intensity threshold (CtFL− CtDelta5). Negative values indicate that the FL form was more abundant than the Δ5ERα and vice versa.
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