Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

ABSTRACTGenome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals, and explore the functional mechanism underlying altered risk at the 12q24 risk region. Our results demonstrate the power of combining genetics, computational genomics and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.

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Chromatin interactome mapping at 139 independent breast cancer risk signals

Genome Biology ◽

10.1186/s13059-019-1877-y ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 8

Author(s):

Jonathan Beesley ◽

Haran Sivakumaran ◽

Mahdi Moradi Marjaneh ◽

Luize G. Lima ◽

Kristine M. Hillman ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Target Genes ◽

Cancer Susceptibility ◽

Association Studies ◽

Breast Cancer Cell Lines ◽

Open Chromatin ◽

Genome Wide Association Studies ◽

Candidate Target

Abstract Background Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. Results We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region. Conclusions Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.

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Capture Hi-C identifies putative target genes at 33 breast cancer risk loci

Nature Communications ◽

10.1038/s41467-018-03411-9 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 46

Author(s):

Joseph S. Baxter ◽

Olivia C. Leavy ◽

Nicola H. Dryden ◽

Sarah Maguire ◽

Nichola Johnson ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Target Genes ◽

Putative Target

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Functional annotation of breast cancer risk loci: current progress and future directions

British Journal of Cancer ◽

10.1038/s41416-021-01612-6 ◽

2021 ◽

Author(s):

Shirleny Romualdo Cardoso ◽

Andrea Gillespie ◽

Syed Haider ◽

Olivia Fletcher

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Target Genes ◽

Regulatory Sequences ◽

Fine Scale ◽

Functional Variants ◽

Putative Target ◽

Causal Variants ◽

Fine Scale Mapping

AbstractGenome-wide association studies coupled with large-scale replication and fine-scale mapping studies have identified more than 150 genomic regions that are associated with breast cancer risk. Here, we review efforts to translate these findings into a greater understanding of disease mechanism. Our review comes in the context of a recently published fine-scale mapping analysis of these regions, which reported 352 independent signals and a total of 13,367 credible causal variants. The vast majority of credible causal variants map to noncoding DNA, implicating regulation of gene expression as the mechanism by which functional variants influence risk. Accordingly, we review methods for defining candidate-regulatory sequences, methods for identifying putative target genes and methods for linking candidate-regulatory sequences to putative target genes. We provide a summary of available data resources and identify gaps in these resources. We conclude that while much work has been done, there is still much to do. There are, however, grounds for optimism; combining statistical data from fine-scale mapping with functional data that are more representative of the normal “at risk” breast, generated using new technologies, should lead to a greater understanding of the mechanisms that influence an individual woman’s risk of breast cancer.

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Identifying breast cancer risk loci by global differential allele-specific expression (DASE) analysis in mammary epithelial transcriptome

BMC Genomics ◽

10.1186/1471-2164-13-570 ◽

2012 ◽

Vol 13 (1) ◽

pp. 570 ◽

Cited By ~ 13

Author(s):

Chuan Gao ◽

Karthik Devarajan ◽

Yan Zhou ◽

Carolyn M Slater ◽

Mary B Daly ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Mammary Epithelial ◽

Specific Expression ◽

Allele Specific Expression ◽

Allele Specific

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Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

10.1101/777318 ◽

2019 ◽

Author(s):

Ana Jacinta-Fernandes ◽

Joana M. Xavier ◽

Ramiro Magno ◽

Joel G. Lage ◽

Ana-Teresa Maia

Keyword(s):

Breast Cancer ◽

Target Genes ◽

Association Studies ◽

Mirna Gene ◽

Genome Wide Association Studies ◽

Binding Prediction ◽

Cis Regulation ◽

Genome Wide ◽

Candidate Target ◽

Allele Specific

ABSTRACTMost breast cancer (BC) risk-associated variants (raSNPs) identified in genome-wide association studies (GWAS) are believed to cis-regulate the expression of genes. We hypothesise that cis-regulatory variants contributing to disease risk may be affecting miRNA genes and/or miRNA-binding. To test this we adapted two miRNA-binding prediction algorithms — TargetScan and miRanda — to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant (P ≤ 5 × 10−8) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3’UTRs of putative miRNA target genes were predicted to alter miRNA∷mRNA pair binding stability in five candidate target genes. Of these, we propose RNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and re-inforce the role of miRNA mediated cis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting cis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.

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Fine-mapping of 150 breast cancer risk regions identifies 178 high confidence target genes

10.1101/521054 ◽

2019 ◽

Cited By ~ 2

Author(s):

Laura Fachal ◽

Hugues Aschard ◽

Jonathan Beesley ◽

Daniel R. Barnes ◽

Jamie Allen ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Target Genes ◽

Association Studies ◽

Chromatin Interaction ◽

Dna Integrity ◽

Genomic Feature ◽

Genome Wide Association Studies ◽

Causal Variants

ABSTRACTGenome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities (HPPs) of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the 178 highest confidence target genes.

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Allele-specific regulation of FGFR2 expression is cell type-dependent and may increase breast cancer risk through a paracrine stimulus involving FGF10

Breast Cancer Research ◽

10.1186/bcr2917 ◽

2011 ◽

Vol 13 (4) ◽

Cited By ~ 24

Author(s):

Petra EA Huijts ◽

Minka van Dongen ◽

Moniek CM de Goeij ◽

Adrian J van Moolenbroek ◽

Freek Blanken ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Increase Breast Cancer Risk ◽

Cell Type ◽

Allele Specific ◽

Specific Regulation

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Effects of Endocrine Disruptors o,p′-Dichlorodiphenyltrichloroethane, p,p′-Dichlorodiphenyltrichloroethane, and Endosulfan on the Expression of Estradiol-, Progesterone-, and Testosterone-Responsive MicroRNAs and Their Target Genes in MCF-7 Cells

Toxics ◽

10.3390/toxics10010025 ◽

2022 ◽

Vol 10 (1) ◽

pp. 25

Author(s):

Tatiana Kalinina ◽

Vladislav Kononchuk ◽

Lyubov Klyushova ◽

Lyudmila Gulyaeva

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Endocrine Disruptors ◽

Target Genes ◽

Breast Carcinogenesis ◽

Expression Levels ◽

Protein Levels ◽

Mcf 7 ◽

In Cells

Many studies have shown that dichlorodiphenyltrichloroethane (DDT) exposure raises breast cancer risk. Another insecticide with similar properties is endosulfan, which has been actively used in agriculture after DDT prohibition. Previously, we have identified some estradiol-, progesterone-, and testosterone-sensitive microRNAs (miRNAs, miRs). Because DDT and endosulfan have estrogenic, antiandrogenic, and antiprogesterone properties, we hypothesized that these miRNAs are affected by the insecticides. We quantified relative levels of miRNAs and expression levels of their target genes in breast cancer MCF-7 cells treated with p,p′-DDT, o,p′-DDT, or endosulfan. We also quantified miR-19b expression, which, as previously shown, is regulated by estrogen. Here, we observed that miR-19b expression increased in response not only to estradiol but also to testosterone and progesterone. Treatment of MCF-7 cells with p,p′-DDT or endosulfan decreased the protein levels of apoptosis regulators TP53INP1 and APAF1. In cells treated with o,p′-DDT, the TP53INP1 amount decreased after 24 h of incubation, but increased after 48 h of incubation with insecticide. OXTR expression, which is known to be associated with breast carcinogenesis, significantly diminished under the exposure of all insecticides. In cells treated with p,p′-DDT or o,p′-DDT, the observed changes were accompanied by alterations of the levels of hormone-responsive miRNAs: miR-324, miR-190a, miR-190b, miR-27a, miR-193b, and miR-19b.

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