Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

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Ottini, S.K. Park, M. Thomassen, P. Hall, A. Meindl, R.K. Schmutzler, A. Droit, G.D. Bader, P.D. Pharoah, F.J. Couch, D.F. Easton, P. Kraft, G. Chenevix-Trench, M. Garciá-Closas, A.C. Antoniou, J. Simard

Research output: Contribution to journalArticlepeer-review

Abstract

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
Original languageEnglish
Pages (from-to)1767-1778
Number of pages12
JournalNature Genetics
Volume49
Issue number12
DOIs
Publication statusPublished - 2017

Keywords

  • ATM protein
  • atrogin 1
  • BRCA1 protein
  • cyclic AMP responsive element binding protein binding protein
  • cyclin E
  • cyclin e1
  • nuclear protein
  • nuclear protein ataxia telangiectasia
  • unclassified drug
  • estrogen receptor
  • adcy3 gene
  • adcy9 gene
  • adult
  • anxa13 gene
  • Article
  • cancer risk
  • cancer susceptibility
  • case control study
  • cdh2 gene
  • cohort analysis
  • computer model
  • controlled study
  • enhancer region
  • estrogen receptor negative breast cancer
  • female
  • gene frequency
  • gene mutation
  • gene replication
  • genetic association
  • genetic correlation
  • genetic risk
  • genetic susceptibility
  • genetic variability
  • genome analysis
  • genome-wide association study
  • genotype
  • haplotype map
  • heritability
  • heterozygote
  • human
  • human cell
  • kdelc2 gene
  • l3mbtl3 gene
  • major clinical study
  • meta analysis (topic)
  • middle aged
  • ncoa1 gene
  • priority journal
  • promoter region
  • quantitative trait locus
  • retrospective study
  • rpl23ap53 gene
  • single nucleotide polymorphism
  • tspan16 gene
  • tumor gene
  • breast tumor
  • Caucasian
  • ethnology
  • genetic predisposition
  • genetics
  • metabolism
  • mutation
  • procedures
  • risk factor
  • BRCA1 Protein
  • Breast Neoplasms
  • European Continental Ancestry Group
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Heterozygote
  • Humans
  • Mutation
  • Polymorphism, Single Nucleotide
  • Receptors, Estrogen
  • Risk Factors

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