The MRPS30 eQTL replicates in a validation cohort

1. The 5p12 breast cancer susceptibility locus is associated with MRPS30 expression in estrogen-receptor positive tumors San Antonio Breast Cancer Symposium December 4-8, 2012 D.A. Quigley1,2, E. Fiorito3, P. Van Loo4, G.G. Alnæs1, T. Fleischer1, D. Zelenieka5, J. Tost5, H.K. Vollan1, A. Hurtado3, A. Balmain2, A.L. Børresen-Dale1, & V. Kristensen1 1Department of Genetics, Institute for Cancer Research, University of Oslo 2Helen Diller Family Comprehensive Cancer Center, UCSF 3 Breast Cancer Research Group, Center for Molecular Medicine, University of Oslo 4Cancer Genome Project, Wellcome Trust Sanger Institute 5Laboratory for Epigenetics, Centre National de Génotypage, CEA-Institute de Génomique • How do common genetic variants affect breast cancer susceptibility? • Many common variants are linked to breast cancer susceptibility, but genome-wide association studies cannot identify causal variations or explain how a locus affects susceptibility • Here we show that the susceptibility locus at 5p12 affects MRPS30 gene expression via estrogen-induced epigenetic changes in the MRPS30promoter region and near the rs7716600 SNP • Genome-wide eQTL analysis of breast tumors • We performed three expression Quantitative Trait Locus (eQTL) studies: • Breast adenocarcinoma, discovery (N=285) • Breast adenocarcinoma, validation (N=235) • Normal breast (N=99) • rs7716600 at 5p12 was linked to MRPS30expression • This locus1 (specifically the AA allele of rs77166002)is associated with estrogen receptor positive breast cancer susceptibility • 1 Stacey et al. Nature Genetics, 2008 • 2 Li et al. Breast Cancer Research & Treatment, 2011 • The MRPS30 eQTL replicates in a validation cohort • 29 discovery eQTL unique to breast cancer were tested in validation • MRPS30 eQTL effect was significant only in ER-positive tumors • AA allele was associated with higher expression of MRPS30 • MRPS30 is estrogen-responsive and correlated with an estrogen signature in ER-positive tumors • Estradiol increased MRPS30 expression in MCF7 cells at 6 hours • However, estradiol decreased MRPS30 expression at 12 hours • rs7716600 is associated with MRPS30 promoter methylation • We analyzed 123 samples from the discovery cohort (Illumina 450 chip) • AA allele was associated with methylation at MRPS30 promoter • ERα and CTCF binding at the MRPS30 promoter and SNP region is affected by estrogen levels • A model for estrogen-dependent influence on MRPS30 expression P = 7 x 10-7 DISCOVERY P = 4 x 10-4 VALIDATION ERα binding at region ERα binding at promoter CTCF binding at region FAIRE at promoter P = 0.10 P = 0.039 P = 0.04 ChIP-PCR signal P = 0.08 ChIP-PCR signal ChIP-PCR signal 45 minutes 3 hours 12 hours 45 minutes promoter region 1 hour 12 hours P = 0.006 P = 0.005 chromosome Fold-change MRPS30 expression P = 0.002 5% FDR cut-off Genome-wide eQTL significance plot showing cis-acting loci affecting gene expression 164 significant loci found (FDR ≤ 5%) 6 hours 12 hours MRPS30 expression in the MCF7 cell line (RT-PCR) Strongest correlations with MRPS30 expression in discovery cohort tumors This presentation is the intellectual property of the author/presenter. Contact dquigley@cc.ucsf.edu for permission to reprint or distribute. SNP and SNP region