Displaying publications 21 - 33 of 33 in total

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  1. Fulltext Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium
    Morra A, Jung AY, Behrens S, Keeman R, Ahearn TU, Anton-Culver H, et al.
    Cancer Epidemiol Biomarkers Prev, 2021 Apr;30(4):623-642.
    PMID: 33500318 DOI: 10.1158/1055-9965.EPI-20-0924
    BACKGROUND: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.

    METHODS: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.

    RESULTS: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (P adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.

    CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.

    IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

  2. Fulltext Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk
    Liu J, Prager-van der Smissen WJC, Collée JM, Bolla MK, Wang Q, Michailidou K, et al.
    Sci Rep, 2020 Jun 16;10(1):9688.
    PMID: 32546843 DOI: 10.1038/s41598-020-65665-y
    In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
  3. Fulltext Two truncating variants in FANCC and breast cancer risk
    Dörk T, Peterlongo P, Mannermaa A, Bolla MK, Wang Q, Dennis J, et al.
    Sci Rep, 2019 08 29;9(1):12524.
    PMID: 31467304 DOI: 10.1038/s41598-019-48804-y
    Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
  4. Fulltext Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
    Machiela MJ, Zhou W, Karlins E, Sampson JN, Freedman ND, Yang Q, et al.
    Nat Commun, 2016 06 13;7:11843.
    PMID: 27291797 DOI: 10.1038/ncomms11843
    To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
  5. Fulltext Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants
    Dadaev T, Saunders EJ, Newcombe PJ, Anokian E, Leongamornlert DA, Brook MN, et al.
    Nat Commun, 2018 06 11;9(1):2256.
    PMID: 29892050 DOI: 10.1038/s41467-018-04109-8
    Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
  6. Fulltext Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci
    Schumacher FR, Al Olama AA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, et al.
    Nat Genet, 2018 07;50(7):928-936.
    PMID: 29892016 DOI: 10.1038/s41588-018-0142-8
    Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.
  7. Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci
    Schumacher FR, Olama AAA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, et al.
    Nat Genet, 2019 02;51(2):363.
    PMID: 30622367 DOI: 10.1038/s41588-018-0330-6
    In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
  8. Fulltext Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
    Baxter JS, Johnson N, Tomczyk K, Gillespie A, Maguire S, Brough R, et al.
    Am J Hum Genet, 2021 Jul 01;108(7):1190-1203.
    PMID: 34146516 DOI: 10.1016/j.ajhg.2021.05.013
    A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).
  9. Fulltext Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer
    Michailidou K, Beesley J, Lindstrom S, Canisius S, Dennis J, Lush MJ, et al.
    Nat Genet, 2015 Apr;47(4):373-80.
    PMID: 25751625 DOI: 10.1038/ng.3242
    Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
  10. Fulltext Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
    Fachal L, Aschard H, Beesley J, Barnes DR, Allen J, Kar S, et al.
    Nat Genet, 2020 01;52(1):56-73.
    PMID: 31911677 DOI: 10.1038/s41588-019-0537-1
    Genome-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 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 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 those potentially causal variants, using gene expression (expression quantitative trait loci), 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 highest-confidence target genes.
  11. Fulltext Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
    Couch FJ, Kuchenbaecker KB, Michailidou K, Mendoza-Fandino GA, Nord S, Lilyquist J, et al.
    Nat Commun, 2016 Apr 27;7:11375.
    PMID: 27117709 DOI: 10.1038/ncomms11375
    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
  12. Fulltext Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer
    Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, et al.
    Nat Genet, 2017 Dec;49(12):1767-1778.
    PMID: 29058716 DOI: 10.1038/ng.3785
    Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
  13. Fulltext Association analysis identifies 65 new breast cancer risk loci
    Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, et al.
    Nature, 2017 Nov 02;551(7678):92-94.
    PMID: 29059683 DOI: 10.1038/nature24284
    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 
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