An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Asaf Wyszynski, Chi-Chen Hong, Kristin Lam, Kyriaki Michailidou, Christian Lytle, Song Yao, Yali Zhang, Manjeet K Bolla, Qin Wang, Nick Orr

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14 Citations (Scopus)

Abstract

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55–0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10−19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10−15 − 5.6 × 10−17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.
Original languageEnglish
Pages (from-to)3863–3876
Number of pages14
JournalHuman Molecular Genetics
Volume25
Issue number17
DOIs
Publication statusPublished - 01 Sep 2016

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    Wyszynski, A., Hong, C-C., Lam, K., Michailidou, K., Lytle, C., Yao, S., Zhang, Y., Bolla, M. K., Wang, Q., & Orr, N. (2016). An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. Human Molecular Genetics, 25(17), 3863–3876. https://doi.org/10.1093/hmg/ddw223