Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

NBCS Collaborators, KConFab Investigators, ABCTB Investigators, Joseph S. Baxter, Nichola Johnson, Katarzyna Tomczyk, Andrea Gillespie, Sarah Maguire, Rachel Brough, Laura Fachal, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. AronsonAnnelie Augustinsson, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Natalia V. Bogdanova, Stig E. Bojesen, Hermann Brenner, Sara Y. Brucker, Qiuyin Cai, Daniele Campa, Federico Canzian, Jose E. Castelao, Tsun L. Chan, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Ji Yeob Choi, Christine L. Clarke, Sarah Colonna, Don M. Conroy, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Laure Dossus, Miriam Dwek, Diana M. Eccles, Arif B. Ekici

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74–0.81, p = 3.1 × 10−31).

Original languageEnglish
Pages (from-to)1190-1203
Number of pages14
JournalAmerican Journal of Human Genetics
Issue number7
StatePublished - Jul 2021


  • Breast Neoplasms/genetics
  • CRISPR-Cas Systems
  • Cell Line
  • Chromosome Mapping
  • Chromosomes, Human, Pair 2
  • Female
  • Genetic Association Studies
  • Genetic Variation
  • Humans
  • Insulin-Like Growth Factor Binding Protein 5/genetics
  • Molecular Sequence Annotation
  • Promoter Regions, Genetic
  • Risk Factors
  • Sequence Deletion


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