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 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 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 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 No Association of the 5′Promoter Region Polymorphism of CYP17 with Breast Cancer Risk in Japan

2000 ◽  
Vol 91 (9) ◽  
pp. 880-885 ◽  
Author(s):  
Nobuyuki Hamajima ◽  
Hiroji Iwata ◽  
Yuichi Obata ◽  
Keitaro Matsuo ◽  
Mitsuhiro Mizutani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Promoter Region

scholarly journals The –553 T/A polymorphism in the promoter region of the FGF2 gene is associated with increased breast cancer risk in Polish women

2015 ◽  
Vol 3 ◽  
pp. 619-627 ◽  
Author(s):  
Jan Rykala ◽  
Karolina Przybylowska ◽  
Ireneusz Majsterek ◽  
Grazyna Pasz-Walczak ◽  
Andrzej Sygut ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Promoter Region

scholarly journals Lack of Association between rs2067474 Polymorphism in Histamine Receptor H2Gene and Breast Cancer in Chinese Han Population

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Wen-Ke Cai ◽  
Jia-Bin Zhang ◽  
Niu-Min Wang ◽  
Ying-Lin Wang ◽  
Can-Hu Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cancer Patients ◽  
Chinese Han Population ◽  
Clinicopathological Parameters ◽  
Breast Cancer Patients ◽  
Chinese Han ◽  
Enhancer Element ◽  
Han Population

Histamine H2receptor (HRH2) was previously suggested to affect the proliferation of breast cancer cells and disease-free survival of breast cancer patients. Furthermore, a common polymorphism, rs2067474, was identified in an enhancer element of theHRH2gene promoter and was reported to be associated with various diseases including cancer. However, the relationship between this polymorphism and breast cancer risk and malignant degree remains unclear. The aim of this study was to clarify the clinical association of rs2067474 polymorphism with breast cancer. A total of 201 unrelated Chinese Han breast cancer patients and 238 ethnicity-matched health controls were recruited and rs2067474 polymorphism was genotyped. Logistic regression analyses were performed to calculate the odds ratios (ORs) as a measure of association of genotype with breast cancer according to 3 genetic models (dominant, recessive, and additive). Although the percentage of hormone receptor negative cases tended to be higher in AA genotypes, we did not find any significant associations of rs2067474 polymorphism with breast cancer risk or with related clinicopathological parameters in the present study, which indicates that rs2067474 polymorphism ofHRH2gene might not be a risk factor in the development of breast cancer in Chinese Han population.

scholarly journals Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus: Putative Functional Variants Differentially Bind FOXA1 and E2F1

2013 ◽  
Vol 93 (6) ◽  
pp. 1046-1060 ◽  
Author(s):  
Kerstin B. Meyer ◽  
Martin O’Reilly ◽  
Kyriaki Michailidou ◽  
Saskia Carlebur ◽  
Stacey L. Edwards ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Fine Scale ◽  
Functional Variants ◽  
Risk Locus ◽  
Fine Scale Mapping

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.

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