Breast cancer risk–associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression



Genome-wide association studies (GWAS) have identified thousands of SNPs that are associated with human traits and diseases. But, because the vast majority of these SNPs are located in non-coding regions of the genome, the mechanisms by which they promote disease risk have remained elusive. Employing a new methodology that combines cistromics, epigenomics and genotype imputation, we annotate the non-coding regions of the genome in breast cancer cells and systematically identify the functional nature of SNPs associated with breast cancer risk. Our results show that breast cancer risk–associated SNPs are enriched in the cistromes of FOXA1 and ESR1 and the epigenome of histone H3 lysine 4 monomethylation (H3K4me1) in a cancer- and cell type–specific manner. Furthermore, the majority of the risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, thereby resulting in allele-specific gene expression, which is exemplified by the effect of the rs4784227 SNP on the TOX3 gene within the 16q12.1 risk locus.

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Figure 1: The breast cancer AVS is enriched in the cistromes of FOXA1 and ESR1.
Figure 2: Enrichment of the breast cancer AVS is factor, cell type and cancer type specific.
Figure 3: The intragenomic replicates (IGR) method.
Figure 4: The breast cancer–associated SNP rs4784227 modulates FOXA1 affinity by altering the FKH motif.
Figure 5: The breast cancer AVS is enriched for affinity-modulating SNPs.
Figure 6: The breast cancer–associated SNP rs4784227 disrupts enhancer function through FOXA1 affinity modulation.
Figure 7: The breast cancer–associated SNP rs4784227 affects cell proliferation by disrupting TOX3 gene expression.
Figure 8

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We thank M. Brown, M.L. Freedman and M. Lemaire for discussions, as well as B.G. Neel and R. Marcotte for technical assistance. We acknowledge support from the US National Cancer Institute (NCI; 2P30CA023108-32), the American Cancer Society (ACS; IRG-82-003-27 to M.L.), the US National Institutes of Health (NIH; R01LM009012 to J.H.M. and R01CA155004 to M.L.) and the Princess Margaret Hospital Foundation (M.L.).

Author information




All experiments were conceived by R.C.-S., X.Z., J.E., M.D.C., J.H.M. and M.L. Experiments were conducted by X.Z. and J.B.W. Computational methods were conceived and implemented by R.C.-S. with help from J.H.M. and M.L. Computational analysis was conducted by R.C.-S. and S.D.B. The manuscript was written by R.C.-S., X.Z. and M.L. with help from J.E., M.D.C. and J.H.M. Figures were designed and prepared by R.C.-S. and X.Z.

Corresponding authors

Correspondence to Jason H Moore or Mathieu Lupien.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Tables 2–10 and 15–21 (PDF 308 kb)

Supplementary Table 1

LDXI: BCa AVS. (XLSX 84 kb)

Supplementary Table 11

LDXI: DNase filtered BCa AVS. (XLSX 51 kb)

Supplementary Table 12

LDXI: Prostate cancer AVS. (XLSX 87 kb)

Supplementary Table 13

LDXI: Bone mineral density AVS. (XLSX 72 kb)

Supplementary Table 14

LDXI: Colorectal cancer AVS. (XLSX 67 kb)

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Cowper-Sal·lari, R., Zhang, X., Wright, J. et al. Breast cancer risk–associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nat Genet 44, 1191–1198 (2012).

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