Displaying publications 1 - 20 of 71 in total

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  1. Matejcic M, Saunders EJ, Dadaev T, Brook MN, Wang K, Sheng X, et al.
    Nat Commun, 2019 01 17;10(1):382.
    PMID: 30655571 DOI: 10.1038/s41467-019-08293-z
    The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.
  2. Huynh-Le MP, Karunamuni R, Fan CC, Asona L, Thompson WK, Martinez ME, et al.
    Prostate Cancer Prostatic Dis, 2022 Apr;25(4):755-761.
    PMID: 35152271 DOI: 10.1038/s41391-022-00497-7
    BACKGROUND: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.

    METHODS: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.

    RESULTS: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.

    CONCLUSIONS: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

  3. Matejcic M, Saunders EJ, Dadaev T, Brook MN, Wang K, Sheng X, et al.
    Nat Commun, 2018 Nov 05;9(1):4616.
    PMID: 30397198 DOI: 10.1038/s41467-018-06863-1
    Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p 
  4. Adams CD, Richmond R, Ferreira DLS, Spiller W, Tan V, Zheng J, et al.
    Cancer Epidemiol Biomarkers Prev, 2019 Jan;28(1):208-216.
    PMID: 30352818 DOI: 10.1158/1055-9965.EPI-18-0079
    BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).

    METHODS: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.

    RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.

    CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.

    IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

  5. Huynh-Le MP, Fan CC, Karunamuni R, Thompson WK, Martinez ME, Eeles RA, et al.
    Nat Commun, 2021 02 23;12(1):1236.
    PMID: 33623038 DOI: 10.1038/s41467-021-21287-0
    Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p 
  6. Darst BF, Shen J, Madduri RK, Rodriguez AA, Xiao Y, Sheng X, et al.
    Am J Hum Genet, 2023 Jul 06;110(7):1200-1206.
    PMID: 37311464 DOI: 10.1016/j.ajhg.2023.05.010
    Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.
  7. Darst BF, Shen J, Madduri RK, Rodriguez AA, Xiao Y, Sheng X, et al.
    medRxiv, 2023 May 15.
    PMID: 37292833 DOI: 10.1101/2023.05.12.23289860
    Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.
  8. 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.
  9. 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.
  10. 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.
  11. Conti DV, Darst BF, Moss LC, Saunders EJ, Sheng X, Chou A, et al.
    Nat Genet, 2021 Jan;53(1):65-75.
    PMID: 33398198 DOI: 10.1038/s41588-020-00748-0
    Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
  12. Wang A, Shen J, Rodriguez AA, Saunders EJ, Chen F, Janivara R, et al.
    Nat Genet, 2023 Dec;55(12):2065-2074.
    PMID: 37945903 DOI: 10.1038/s41588-023-01534-4
    The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
  13. Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Bergauer T, Dragicevic M, et al.
    Phys Rev Lett, 2015 Feb 13;114(6):061801.
    PMID: 25723204
    A search for new long-lived particles decaying to leptons is presented using proton-proton collisions produced by the LHC at √[s]=8  TeV. Data used for the analysis were collected by the CMS detector and correspond to an integrated luminosity of 19.7  fb(-1). Events are selected with an electron and muon with opposite charges that both have transverse impact parameter values between 0.02 and 2 cm. The search has been designed to be sensitive to a wide range of models with nonprompt e-μ final states. Limits are set on the "displaced supersymmetry" model, with pair production of top squarks decaying into an e-μ final state via R-parity-violating interactions. The results are the most restrictive to date on this model, with the most stringent limit being obtained for a top squark lifetime corresponding to cτ=2  cm, excluding masses below 790 GeV at 95% confidence level.
  14. Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Bergauer T, Dragicevic M, et al.
    Phys Rev Lett, 2015 Feb 6;114(5):051801.
    PMID: 25699433
    A study of vector boson scattering in pp collisions at a center-of-mass energy of 8 TeV is presented. The data sample corresponds to an integrated luminosity of 19.4  fb(-1) collected with the CMS detector. Candidate events are selected with exactly two leptons of the same charge, two jets with large rapidity separation and high dijet mass, and moderate missing transverse energy. The signal region is expected to be dominated by electroweak same-sign W-boson pair production. The observation agrees with the standard model prediction. The observed significance is 2.0 standard deviations, where a significance of 3.1 standard deviations is expected based on the standard model. Cross section measurements for W(±)W(±) and WZ processes in the fiducial region are reported. Bounds on the structure of quartic vector-boson interactions are given in the framework of dimension-eight effective field theory operators, as well as limits on the production of doubly charged Higgs bosons.
  15. Chatrchyan S, Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Bergauer T, et al.
    Phys Rev Lett, 2014 Apr 25;112(16):161802.
    PMID: 24815637
    Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top quark (the top squark) and the Higgs boson (Higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7  fb-1 of proton-proton collision data at s=8  TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the top squark mass below 360 to 410 GeV, depending on the Higgsino mass.
  16. CMS Collaboration, Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Bergauer T, et al.
    Eur Phys J C Part Fields, 2014 09 26;74(9):3036.
    PMID: 25814912
    Searches for the direct electroweak production of supersymmetric charginos, neutralinos, and sleptons in a variety of signatures with leptons and [Formula: see text], [Formula: see text], and Higgs bosons are presented. Results are based on a sample of proton-proton collision data collected at center-of-mass energy [Formula: see text] with the CMS detector in 2012, corresponding to an integrated luminosity of 19.5 [Formula: see text]. The observed event rates are in agreement with expectations from the standard model. These results probe charginos and neutralinos with masses up to 720 [Formula: see text], and sleptons up to 260 [Formula: see text], depending on the model details.
  17. Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Bergauer T, Dragicevic M, et al.
    Eur Phys J C Part Fields, 2014 10 15;74(10):3076.
    PMID: 25814871
    Observation of the diphoton decay mode of the recently discovered Higgs boson and measurement of some of its properties are reported. The analysis uses the entire dataset collected by the CMS experiment in proton-proton collisions during the 2011 and 2012 LHC running periods. The data samples correspond to integrated luminosities of 5.1[Formula: see text]at [Formula: see text] and 19.7[Formula: see text]at 8[Formula: see text] . A clear signal is observed in the diphoton channel at a mass close to 125[Formula: see text] with a local significance of [Formula: see text], where a significance of [Formula: see text] is expected for the standard model Higgs boson. The mass is measured to be [Formula: see text] , and the best-fit signal strength relative to the standard model prediction is [Formula: see text][Formula: see text][Formula: see text]. Additional measurements include the signal strength modifiers associated with different production mechanisms, and hypothesis tests between spin-0 and spin-2 models.
  18. Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2016 Feb 19;116(7):071801.
    PMID: 26943527 DOI: 10.1103/PhysRevLett.116.071801
    A search for narrow resonances in proton-proton collisions at sqrt[s]=13  TeV is presented. The invariant mass distribution of the two leading jets is measured with the CMS detector using a data set corresponding to an integrated luminosity of 2.4  fb^{-1}. The highest observed dijet mass is 6.1 TeV. The distribution is smooth and no evidence for resonant particles is observed. Upper limits at 95% confidence level are set on the production cross section for narrow resonances with masses above 1.5 TeV. When interpreted in the context of specific models, the limits exclude string resonances with masses below 7.0 TeV, scalar diquarks below 6.0 TeV, axigluons and colorons below 5.1 TeV, excited quarks below 5.0 TeV, color-octet scalars below 3.1 TeV, and W^{'} bosons below 2.6 TeV. These results significantly extend previously published limits.
  19. Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2016 Jan 22;116(3):032301.
    PMID: 26849587 DOI: 10.1103/PhysRevLett.116.032301
    The production cross sections of the B^{+}, B^{0}, and B_{s}^{0} mesons, and of their charge conjugates, are measured via exclusive hadronic decays in p+Pb collisions at the center-of-mass energy sqrt[s_{NN}]=5.02  TeV with the CMS detector at the CERN LHC. The data set used for this analysis corresponds to an integrated luminosity of 34.6  nb^{-1}. The production cross sections are measured in the transverse momentum range between 10 and 60  GeV/c. No significant modification is observed compared to proton-proton perturbative QCD calculations scaled by the number of incoherent nucleon-nucleon collisions. These results provide a baseline for the study of in-medium b quark energy loss in Pb+Pb collisions.
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