Two distinct mechanisms underlie estrogen-receptor-negative breast cancer susceptibility at the 2p23.2 locus
| العنوان: | Two distinct mechanisms underlie estrogen-receptor-negative breast cancer susceptibility at the 2p23.2 locus |
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| المؤلفون: | Nicholas T. Woods, Paulo C Lyra, Alvaro N.A. Monteiro, Marcelo A. Carvalho, Carly M. Harro, Thales C. Nepomuceno, Fergus J. Couch, Leticia Batista Azevedo Rangel, Gustavo Mendoza-Fandiño, Xueli Li |
| المصدر: | Eur J Hum Genet |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Untranslated region, Genetics, Breast Neoplasms, Estrogens, Triple Negative Breast Neoplasms, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Regulatory sequence, Humans, Female, Genetic Predisposition to Disease, Ectopic expression, Transcription factor, Gene, Genetics (clinical), Genome-Wide Association Study |
| الوصف: | Genome wide-association studies (GWAS) have established over 400 breast cancer risk loci defined by common single nucleotide polymorphisms (SNPs), including several associated with estrogen-receptor (ER)-negative disease. Most of these loci have not been studied systematically and the mechanistic underpinnings of risk are largely unknown. Here we explored the landscape of genomic features at an ER-negative breast cancer susceptibility locus at chromosome 2p23.2 and assessed the functionality of 81 SNPs with strong evidence of association from previous fine mapping. Five candidate regulatory regions containing risk-associated SNPs were identified. Regulatory Region 1 in the first intron of WDR43 contains SNP rs4407214, which showed allele-specific interaction with the transcription factor USF1 in in vitro assays. CRISPR-mediated disruption of Regulatory Region 1 led to expression changes in the neighboring PLB1 gene, suggesting that the region acts as a distal enhancer. Regulatory Regions 2, 4, and 5 did not provide sufficient evidence for functionality in in silico and experimental analyses. Two SNPs (rs11680458 and rs1131880) in Regulatory Region 3, mapping to the seed region for miRNA-recognition sites in the 3' untranslated region of WDR43, showed allele-specific effects of ectopic expression of miR-376 on WDR43 expression levels. Taken together, our data suggest that risk of ER-negative breast cancer associated with the 2p23.2 locus is likely driven by a combinatorial effect on the regulation of WDR43 and PLB1. |
| تدمد: | 1476-5438 1018-4813 1168-0458 |
| DOI: | 10.1038/s41431-021-01005-6 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2e52edcffeda59cf35a688dbc53824c5 https://doi.org/10.1038/s41431-021-01005-6 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2e52edcffeda59cf35a688dbc53824c5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765438 10184813 11680458 |
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| DOI: | 10.1038/s41431-021-01005-6 |