scholarly journals Non-coding RNAs underlie genetic predisposition to breast cancer

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Mahdi Moradi Marjaneh ◽  
Jonathan Beesley ◽  
Tracy A. O’Mara ◽  
Pamela Mukhopadhyay ◽  
Lambros T. Koufariotis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Complex Traits ◽  
Regulatory Elements ◽  
Chromatin Interaction ◽  
Alternative Mechanism ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Non Coding Rnas

Abstract Background Genetic variants identified through genome-wide association studies (GWAS) are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, the contribution of non-coding RNAs to complex traits is not clear. Results Using targeted RNA sequencing, we systematically annotated multi-exonic non-coding RNA (mencRNA) genes transcribed from 1.5-Mb intervals surrounding 139 breast cancer GWAS signals and assessed their contribution to breast cancer risk. We identify more than 4000 mencRNA genes and show their expression distinguishes normal breast tissue from tumors and different breast cancer subtypes. Importantly, breast cancer risk variants, identified through genetic fine-mapping, are significantly enriched in mencRNA exons, but not the promoters or introns. eQTL analyses identify mencRNAs whose expression is associated with risk variants. Furthermore, chromatin interaction data identify hundreds of mencRNA promoters that loop to regions that contain breast cancer risk variants. Conclusions We have compiled the largest catalog of breast cancer-associated mencRNAs to date and provide evidence that modulation of mencRNAs by GWAS variants may provide an alternative mechanism underlying complex traits.

scholarly journals Candidate Causal Variants at the 8p12 Breast Cancer Risk Locus Regulate DUSP4

2019 ◽  
Author(s):  
Dylan M. Glubb ◽  
Wei Shi ◽  
Jonathan Beesley ◽  
Laura Fachal ◽  
Jayne-Louise Pritchard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Promoter Region ◽  
Risk Allele ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Enhancer Element ◽  
Causal Variants ◽  
Risk Locus

Genome-wide association studies have revealed a locus at 8p12 that is associated with breast cancer risk. Fine-mapping of this locus identified 16 candidate causal variants (CCVs). However, as these variants are intergenic, their function is unclear. To map chromatin looping from this risk locus to a previously identified candidate target gene, DUSP4, we performed chromatin conformation capture analyses in normal and tumoral breast cell lines. We identified putative regulatory elements, containing CCVs, that loop to the DUSP4 promoter region. Using reporter gene assays, we found that the risk allele of CCV rs7461885 reduced the activity of a DUSP4 enhancer element, consistent with the function of DUSP4 as a tumor suppressor gene. Furthermore, the risk allele of CCV rs12155535, located in another DUSP4 enhancer element, was negatively correlated with looping of this element to the DUSP4 promoter region, suggesting that this allele would be associated with reduced expression. These findings provide the first evidence that CCV risk alleles downregulate DUSP4 expression, suggesting that this gene is a regulatory target of the 8p12 breast cancer risk locus.

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

2019 ◽  
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.

scholarly journals Identifying 31 novel breast cancer susceptibility loci using data from genome-wide association studies conducted in Asian and European women

2019 ◽  
Author(s):  
Xiang Shu ◽  
Jirong Long ◽  
Qiuyin Cai ◽  
Sun-Seog Kweon ◽  
Ji-Yeob Choi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Asian Populations ◽  
Risk Variants ◽  
Genome Wide ◽  
European Women

ABSTRACTCommon genetic variants in 183 loci have been identified in relation to breast cancer risk in genome-wide association studies (GWAS). These risk variants combined explain only a relatively small proportion of breast cancer heritability, particularly in Asian populations. To search for additional genetic susceptibility loci for breast cancer, we performed a meta-analysis of data from GWAS conducted in Asians (24,206 cases and 24,775 controls). Variants showing an association with breast cancer risk at P < 0.01 were evaluated in GWAS conducted in European women including 122,977 cases and 105,974 controls. In the combined analysis of data from both Asian and European women, the lead variant in 28 loci not previously reported showed an association with breast cancer risk at P < 5 ×10−8. In the meta-analysis of all GWAS data from Asian and European descendants, we identified SNPs in three additional loci in association with breast cancer risk at P < 5 ×10−8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). Expression quantitative trait locus (eQTL) and gene-based analyses provided evidence for the possible involvement of the YBEY, MAN2C1, SNUPN, TBX1, SEMA4A, STC1, MUTYH, LOXL2, and LINC00886 genes underlying the associations observed in eight of these 28 newly identified risk loci. In addition, we replicated the association for 78 of the 166 previously reported risk variants at P < 0.05 in women of Asian descent using GWAS data. These findings improve our understanding of breast cancer genetics and etiology and extend to Asian populations previous findings from studies of European women.

scholarly journals Candidate Causal Variants at the 8p12 Breast Cancer Risk Locus Regulate DUSP4

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 170
Author(s):  
Dylan M. Glubb ◽  
Wei Shi ◽  
Jonathan Beesley ◽  
Laura Fachal ◽  
Jayne-Louise Pritchard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Promoter Region ◽  
Risk Allele ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Enhancer Element ◽  
Causal Variants ◽  
Risk Locus

Genome-wide association studies have revealed a locus at 8p12 that is associated with breast cancer risk. Fine-mapping of this locus identified 16 candidate causal variants (CCVs). However, as these variants are intergenic, their function is unclear. To map chromatin looping from this risk locus to a previously identified candidate target gene, DUSP4, we performed chromatin conformation capture analyses in normal and tumoural breast cell lines. We identified putative regulatory elements, containing CCVs, which looped to the DUSP4 promoter region. Using reporter gene assays, we found that the risk allele of CCV rs7461885 reduced the activity of a DUSP4 enhancer element, consistent with the function of DUSP4 as a tumour suppressor gene. Furthermore, the risk allele of CCV rs12155535, located in another DUSP4 enhancer element, was negatively correlated with looping of this element to the DUSP4 promoter region, suggesting that this allele would be associated with reduced expression. These findings provide the first evidence that CCV risk alleles downregulate DUSP4 expression, suggesting that this gene is a regulatory target of the 8p12 breast cancer risk locus.

scholarly journals Identification of novel common breast cancer risk variants at the 6q25 locus among Latinas

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Joshua Hoffman ◽  
◽  
Laura Fejerman ◽  
Donglei Hu ◽  
Scott Huntsman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Risk Variants

scholarly journals Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors

2015 ◽  
Vol 24 (25) ◽  
pp. 7421-7431 ◽  
Author(s):  
Jennifer L. Caswell ◽  
Roman Camarda ◽  
Alicia Y. Zhou ◽  
Scott Huntsman ◽  
Donglei Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Risk Variants ◽  
Isoform Expression

FGFR2 genotype and risk of radiation-associated breast cancer in Hodgkin lymphoma

Blood ◽  
2012 ◽  
Vol 119 (4) ◽  
pp. 1029-1031 ◽  
Author(s):  
Yussanne P. Ma ◽  
Flora E. van Leeuwen ◽  
Rosie Cooke ◽  
Annegien Broeks ◽  
Victor Enciso-Mora ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Hodgkin Lymphoma ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Control Series ◽  
Cancer Risk Factors ◽  
Increased Risk

Abstract Women treated at young ages with supradiaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide association studies have identified 14 independently replicated common single nucleotide polymorphisms that influence breast cancer risk. To examine whether these variants contribute to risk of radiation-associated breast cancer in HL, we analyzed 2 independent case-control series, from the United Kingdom and The Netherlands, totaling 693 HL patients, 232 with breast cancer and 461 without. rs1219648, which annotates the FGFR2 gene, was associated with risk in both series (combined per-allele odds ratio = 1.59, 95% confidence interval: 1.26-2.02; P = .000111). These data provide evidence that genetic variation in FGFR2 influences radiation-induced breast cancer risk.

scholarly journals CRISPR screens identify gene targets and drug repositioning opportunities at breast cancer risk loci

2021 ◽  
Author(s):  
Natasha K Tuano ◽  
Jonathan Beesley ◽  
Murray Manning ◽  
Wei Shi ◽  
Luis Malver-Ortega ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Risk ◽  
Drug Repositioning ◽  
Association Studies ◽  
Drug Repurposing ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Genome Wide ◽  
Causal Variants ◽  
Cancer Phenotypes

Genome-wide association studies (GWAS) have identified >200 loci associated with breast cancer (BC) risk. The majority of candidate causal variants (CCVs) are in non-coding regions and are likely to modulate cancer risk by regulating gene expression. We recently developed a scoring system, INQUISIT, to predict candidate risk genes at BC-risk loci. Here, we used pooled CRISPR activation and suppression screens to validate INQUISIT predictions, and to define the cancer phenotypes they mediate. We measured proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on the DNA damage response. We performed 60 CRISPR screens and identified 21 high-confidence INQUISIT predictions that mediate a cancer phenotype. We validated the direct regulation of a subset of genes by BC-risk variants using HiCHIP and CRISPRqtl. Furthermore, we show the utility of expression profiling for drug repurposing against these targets. We provide a platform for identifying gene targets of risk variants, and lay a blueprint of interventions for BC risk reduction and treatment.

scholarly journals Chromatin interactome mapping at 139 independent breast cancer risk signals

2019 ◽  
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

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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