The MRPS30 eQTL replicates in a validation cohort
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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 The 5p12 breast cancer susceptibility locus is associated with MRPS30 expression in estrogen-receptor positive tumors to 3 , P. Van Loo 4 , G.G. Alnæs 1 , T. Fleischer 1 , D. Zelenieka 5 , J. Tost 5 , H.K. Vollan 1 , A. Hurtado 3 , A. Balmain 2 , A.L. Børresen-Dale 1 , & V. Kristensen 1 ute for Cancer Research, University of Oslo 2 Helen Diller Family Comprehensive Cancer Center, UCSF 3 Breast Cancer Research Group, Center for Molecular Medicine, University of Oslo e Trust Sanger Institute 5 Laboratory 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 MRPS30 promoter 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 MRPS30 expression • This locus 1 (specifically the AA allele of rs7716600 2 ) is associated with 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 San Antonio Breast Cancer Symposium December 4-8, 2012 This presentation is the intellectual property of the author/presente Contact [email protected] for permission to reprint or distribut de eQTL significance plot showing cis-acting loci affecting gene expression ficant loci found (FDR ≤ 5%) 5% FDR cut-off ER-positive ER-negative symbol rho P rho P SLC39A6 0.50 2x10 -17 0.23 0.02 TPRG1 0.48 2x10 -15 -0.12 0.28 ESR1 0.45 2x10 -14 0.04 0.70 P4HTM 0.44 5x10 -14 0.10 0.33 CA12 0.44 8x10 -14 -0.06 0.59 MAGED2 0.44 2x10 -13 0.09 0.41 SIAH2 0.43 5x10 -13 0.30 4x10 -3 ELP2 0.42 6x10 -13 0.27 8x10 -3 HEXIM2 0.41 4x10 -12 -0.02 0.83 C17orf75 0.41 4x10 -12 0.29 5x10 -3 HPN 0.41 6x10 -12 0.09 0.42 GATA3 0.40 4x10 -11 0.04 0.70 WWP1 0.40 1x10 -11 0.02 0.88 SEMA3B 0.40 2x10 -11 NA NA POLB 0.40 2x10 -11 0.37 2x10 -4 COMMD4 0.39 4x10 -11 0.22 0.03 UGCG 0.39 7x10 -11 -0.13 0.22 C6orf211 0.39 9x10 -11 0.24 0.02 FOXA1 0.39 8x10 -11 -0.07 0.49 chromosome Strongest correlations with MRPS30 expression in discovery cohort tumors MRPS30 expression in the MCF7 cell line (RT-PCR) P = 0.039 1 hour 12 hours FAIRE at promoter 45 minutes ERα binding at region P = 0.08 SNP and SNP region DISCOVERY VALIDATION 3 hours 12 hours 45 minutes ERα binding at promoter P = 0.10 P = 0.04 ChIP-PCR signal ChIP-PCR signal promoterregion CTCF binding at region ChIP-PCR signal P = 0.006 P = 0.005 P = 0.002 Fold-change MRPS30 expression 12 hours 6 hours P = 4 x 10 -4 P = 7 x 10 -7
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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. - PowerPoint PPT Presentation
Transcript of The MRPS30 eQTL replicates in a validation cohort
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
The 5p12 breast cancer susceptibility locus is associated with MRPS30 expression in estrogen-receptor positive tumorsD.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 MRPS30 promoter region and near the rs7716600 SNP
Genome-wide eQTL analysis of breast tumorsWe 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 MRPS30 expression• This locus1 (specifically the AA allele of rs77166002) is associated with estrogen receptor positive breast cancer susceptibility
•1 Stacey et al. Nature Genetics, 20082 Li et al. Breast Cancer Research & Treatment, 2011
rs7716600 is associated with MRPS30 promoter methylationWe 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
San Antonio Breast Cancer SymposiumDecember 4-8, 2012
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint or distribute.
Genome-wide eQTL significance plot showing cis-acting loci affecting gene expression 164 significant loci found (FDR ≤ 5%)
5% FDR cut-off ER-positive ER-negative symbol rho P rho PSLC39A6 0.50 2x10-17 0.23 0.02TPRG1 0.48 2x10-15 -0.12 0.28ESR1 0.45 2x10-14 0.04 0.70P4HTM 0.44 5x10-14 0.10 0.33CA12 0.44 8x10-14 -0.06 0.59MAGED2 0.44 2x10-13 0.09 0.41SIAH2 0.43 5x10-13 0.30 4x10-3
ELP2 0.42 6x10-13 0.27 8x10-3
HEXIM2 0.41 4x10-12 -0.02 0.83C17orf75 0.41 4x10-12 0.29 5x10-3
HPN 0.41 6x10-12 0.09 0.42GATA3 0.40 4x10-11 0.04 0.70WWP1 0.40 1x10-11 0.02 0.88SEMA3B 0.40 2x10-11 NA NAPOLB 0.40 2x10-11 0.37 2x10-4
COMMD4 0.39 4x10-11 0.22 0.03UGCG 0.39 7x10-11 -0.13 0.22C6orf211 0.39 9x10-11 0.24 0.02FOXA1 0.39 8x10-11 -0.07 0.49
chromosome
Strongest correlations with MRPS30expression in discovery cohort tumors
MRPS30 expression in the MCF7 cell line (RT-PCR)
P = 0.039
1 hour 12 hours
FAIRE at promoter
45 minutes
ERα binding at region
P = 0.08
SNP and SNP region
DISC
OVE
RYVA
LIDA
TIO
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3 hours 12 hours45 minutes
ERα binding at promoter
P = 0.10
P = 0.04
ChIP
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sign
al
ChIP
-PCR
sign
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promoter region
CTCF binding at region
ChIP
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sign
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P = 0.006P = 0.005
P = 0.002
Fold
-cha
nge
MRP
S30
expr
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12 hours6 hours
P = 4 x 10-4
P = 7 x 10-7
