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

The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, KConFab investigators, KConFab investigators, Australian Ovarian Cancer Study Group, The GENICA Network

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Breast cancer is themost diagnosedmalignancy and the second leading cause of cancermortality 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 ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated withmodified ERa binding andmonoallelic-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 from41 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 locimay bemediating their effect through IGFBP5.

Original languageEnglish (US)
Pages (from-to)3863-3876
Number of pages14
JournalHuman molecular genetics
Volume25
Issue number17
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, KConFab investigators, KConFab investigators, Australian Ovarian Cancer Study Group, & The GENICA Network (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