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  • Blomqvist, Carl  (36)
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  • 1
    Language: English
    In: Nature genetics, July 2018, Vol.50(7), pp.968-978
    Description: The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P 〈 5.82 × 10, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
    Keywords: Breast Neoplasms -- Genetics
    ISSN: 10614036
    E-ISSN: 1546-1718
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  • 2
    Language: English
    In: Nature, 11/2017, Vol.551(7678), pp.92-94
    Description: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P 〈 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
    Keywords: Ancestry ; Cancer ; Gene ; Genetic Variation ; Genome ; Health Risk ; Heritability ; Polymorphism ; Tumor ; Europe ; Far East ; Medicin Och Hälsovetenskap ; Medicinska Och Farmaceutiska Grundvetenskaper ; Medicinsk Genetik ; Medical And Health Sciences ; Basic Medicine ; Medical Genetics ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi ; Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 3
    Description: Breast cancer risk variants identified in genome-wide association studies explain only a small fraction of familial relative risk, and genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from 67 subjects included in the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from 86 subjects included in The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P 〈 5.82×10-6358 , including 14 genes at loci not yet reported for breast cancer risk. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony forming efficiency. Our study provides new insights into breast cancer genetics and biology....
    Keywords: Nbcs Collaborators ; Kconfab/Aocs Investigators
    ISSN: 1061-4036
    Source: DataCite
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  • 4
    Language: English
    In: International Journal of Epidemiology, 10/01/2018
    Description: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
    Keywords: Breast Cancer ; Mendelian Randomization Analysis ; Genetics ; Glucose ; Insulin ; Obesity;
    ISSN: 0300-5771
    E-ISSN: 1464-3685
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  • 5
    In: Journal Of The National Cancer Institute, 2016, Vol. 108(2)
    Description: Background: The K3326X variant in BRCA2 ( BRCA2 *c.9976A〉T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.
    Keywords: Brca Mutations – Health Aspects ; Codons – Properties ; Disease Susceptibility – Genetic Aspects ; Carcinogenesis – Genetic Aspects;
    ISSN: 0027-8874
    E-ISSN: 1460-2105
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  • 6
    In: Nature Genetics, 2016
    Description: We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor alpha ) 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 super(+) or ER super(-)) and human ERBB2 (HER2 super(+) or HER2 super(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER super(-) 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.
    Keywords: Enhancers ; Erbb-2 Protein ; Mammography ; Breast Cancer ; Tumors ; Estrogen Receptors ; Human Genetics ; Protein-Nucleic Acids Association;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 7
    Language: English
    Description: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRS) could improve screening and prevention strategies. Our aim was to develop PRS, optimized for prediction of estrogen receptor (ER) specific disease, from the largest available genome wide association...
    Keywords: Abctb Investigators ; Kconfab/Aocs Investigators ; Nbcs Collaborators ; Humans ; Breast Neoplasms ; Genetic Predisposition To Disease ; Receptors, Estrogen ; Medical History Taking ; Risk Assessment ; Reproducibility Of Results ; Age Factors ; Multifactorial Inheritance ; Polymorphism, Single Nucleotide ; Adult ; Aged ; Aged, 80 And Over ; Middle Aged ; Female
    Source: DSpace@Cambridge
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  • 8
    Language: English
    Description: Breast cancer risk variants identified in genome-wide association studies explain only a small fraction of familial relative risk, and genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study...
    Keywords: Nbcs Collaborators ; Kconfab/Aocs Investigators ; Humans ; Breast Neoplasms ; Genetic Predisposition To Disease ; Risk ; Case-Control Studies ; Gene Expression ; Polymorphism, Single Nucleotide ; Female ; Genome-Wide Association Study ; Transcriptome
    Source: DSpace@Cambridge
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  • 9
    Language: English
    In: Breast Cancer Research, 2016, Vol. 18
    Description: Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P 〈 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P 〈 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
    Keywords: Fine-Scale Mapping ; Genetic Risk Factor ; Pthlh ; Ccdc91 ; Breast Cancer ; Brac1 Mutation Carriers ; Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi ; Medical And Health Sciences ; Basic Medicine ; Medical Genetics ; Medicin Och Hälsovetenskap ; Medicinska Och Farmaceutiska Grundvetenskaper ; Medicinsk Genetik
    ISSN: 1465-5411
    E-ISSN: 1465542X
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  • 10
    Language: English
    In: Breast Cancer Research, 2016-06, Vol.18(1), pp.64
    Description: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.
    ISSN: 1465-542X
    Source: KU Leuven Association
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