Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.
Change log
Authors
Dunning, Alison M
Michailidou, Kyriaki
Kuchenbaecker, Karoline B
Thompson, Deborah https://orcid.org/0000-0003-1465-5799
French, Juliet D
Abstract
We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
Description
Keywords
Base Sequence, Breast Neoplasms, Carrier Proteins, Cell Cycle Proteins, Chromosomes, Human, Pair 6, Estrogen Receptor alpha, Female, Gene Expression, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Phenotype, Polymorphism, Single Nucleotide, Protein Binding, Risk Factors
Journal Title
Nat Genet
Conference Name
Journal ISSN
1061-4036
1546-1718
1546-1718
Volume Title
48
Publisher
Springer Science and Business Media LLC
Publisher DOI
Sponsorship
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148537)
National Cancer Institute (U19CA148065)
Medical Research Council (MR/N003284/1)
Medical Research Council (G0401527)
Cancer Research Uk (None)
Cancer Research Uk (None)
European Commission (223175)
Cancer Research UK (10710)
Cancer Research UK (12014)
Cancer Research UK (10118)
Medical Research Council (G0401527/1)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research UK (16565)
National Cancer Institute (U19CA148537)
National Cancer Institute (U19CA148065)
Medical Research Council (MR/N003284/1)
Medical Research Council (G0401527)
Cancer Research Uk (None)
Cancer Research Uk (None)
European Commission (223175)
Cancer Research UK (10710)
Cancer Research UK (12014)
Cancer Research UK (10118)
Medical Research Council (G0401527/1)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research UK (16565)