The majority of breast cancer risk alleles affect FOXA1 chromatin affinity.

  • Major finding: The majority of breast cancer risk alleles affect FOXA1 chromatin affinity.

  • Clinical relevance: A risk SNP that increases FOXA1 enhancer binding suppresses the putative tumor suppressor TOX3.

  • Impact: Analysis of genomic features associated with linked SNPs will aid functional characterization of risk loci.

The vast majority of cancer-associated single-nucleotide polymorphisms (SNP) identified in genome-wide association studies map to noncoding regions, hindering their functional classification. Growing evidence suggests that risk-associated SNPs may affect the activity of lineage-specific regulatory elements. Breast cancer provides a unique opportunity to study the effect of SNPs on regulatory regions because cell-specific binding of the pioneer factor forkhead box A1 (FOXA1) and estrogen receptor α (ERα) at enhancer regions is thought to contribute to disease progression. Cowper-Sal Lari and colleagues first used haplotype data to expand the list of breast cancer–associated SNPs and identified clusters of SNPs in linkage disequilibrium. Integration of these variant clusters with cistromic and epigenomic maps revealed that approximately 40% of the clusters were significantly and specifically associated with FOXA1 and ERα binding and histone H3 lysine 4 monomethylation (an epigenetic feature predominantly associated with enhancer regions) in breast cancer cells. The effect of reference and variant alleles on FOXA1 binding affinity was then determined computationally by averaging FOXA1 binding at various DNA sequences across the genome. Strikingly, most of the variant clusters contained SNPs that were predicted to affect FOXA1 binding affinity. An allele-specific increase in FOXA1 binding to chromatin was validated in the majority of breast cancer–associated SNPs, including rs4784227, a SNP lying in a regulatory element upstream of the TOX3 gene. This element was shown to physically interact with the TOX3 promoter, and the variant allele was significantly associated with decreased TOX3 expression. Knockdown of TOX3 significantly increased breast cancer cell proliferation, indicating that the variant allele of rs4784227 SNP may increase breast cancer risk by downregulating TOX3 tumor-suppressor activity. The integration of genomewide data with disease-associated variants and linked SNPs can thus help assign functions to cancer risk alleles.

Cowper-Sal Lari R, Zhang X, Wright JB, Bailey SD, Cole MD, Eeckhoute J, et al. Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nat Genet 2012 Sept 23 [Epub ahead of print].

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