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2.
  • Michailidou, Kyriaki, et al. (författare)
  • Association analysis identifies 65 new breast cancer risk loci
  • 2017
  • Ingår i: Nature. - 1476-4687. ; 551:7678, s. 92-
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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5.
  • Ding, Yuan C., et al. (författare)
  • A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers
  • 2012
  • Ingår i: Cancer Epidemiology Biomarkers & Prevention. - American Association for Cancer Research. - 1538-7755. ; 21:8, s. 1362-1370
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P-difference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). Conclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(8); 1362-70. (C)2012 AACR.
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6.
  • Engel, Christoph, et al. (författare)
  • Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
  • 2010
  • Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 19:11, s. 2859-68
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population. METHODS: To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). RESULTS: The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; P(trend) = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; P(trend) = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers. CONCLUSIONS: CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers. Impact: The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev; 19(11); 2859-68. ©2010 AACR.
7.
  • Ferreira, Manuel A., et al. (författare)
  • Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
  • 2019
  • Ingår i: Nature communications. - 2041-1723. ; 10:1, s. 1741
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer. © 2019, The Author(s).
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  • Kuchenbaecker, Karoline B, et al. (författare)
  • Identification of six new susceptibility loci for invasive epithelial ovarian cancer
  • 2015
  • Ingår i: Nature genetics. - 1546-1718. ; 47:2, s. 164-171
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
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9.
  • Mavaddat, Nasim, et al. (författare)
  • Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)
  • 2012
  • Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 21:1, s. 134-147
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.RESULTS: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%).Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 1-14. ©2011 AACR.
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10.
  • Mavaddat, Nasim, et al. (författare)
  • Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes
  • 2019
  • Ingår i: American journal of human genetics. - 1537-6605. ; 104:1, s. 21-34
  • Tidskriftsartikel (refereegranskat)abstract
    • Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs. © 2018 The Authors
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