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

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  1. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

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  • 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 Aronson
  • Annelie 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
  • Henrik Flyger
  • NBCS Collaborators
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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
JournalAmerican Journal of Human Genetics
Volume108
Issue number7
Pages (from-to)1190-1203
Number of pages14
ISSN0002-9297
DOIs
Publication statusPublished - 1 Jul 2021

    Research areas

  • 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

ID: 67448124