Displaying publications 1 - 20 of 162 in total

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  1. Grootes I, Keeman R, Blows FM, Milne RL, Giles GG, Swerdlow AJ, et al.
    Eur J Cancer, 2022 Sep;173:178-193.
    PMID: 35933885 DOI: 10.1016/j.ejca.2022.06.011
    BACKGROUND: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).

    METHOD: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.

    RESULTS: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.

    CONCLUSION: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.

  2. Veerasamy T, Eugin Simon S, Tan KO
    Int J Biochem Cell Biol, 2021 08;137:106016.
    PMID: 34082133 DOI: 10.1016/j.biocel.2021.106016
    Conventional chemotherapy relies on the cytotoxicity of chemo-drugs to inflict destructive effects on tumor cells. However, as most tumor cells develop resistance to chemo-drugs, small doses of chemo-drugs are unlikely to provide significant clinical benefits in cancer treatment while high doses of chemo-drugs have been shown to impact normal human cells negatively due to the non-specific nature and cytotoxicity associated with chemo-drugs. To overcome this challenge, sensitizations of tumor cells with bioactive molecules that specifically target the pro-survival and pro-apoptosis signaling pathways of the tumor cells are likely to increase the therapeutic impacts and improve the clinical outcomes by reducing the dependency and adverse effects associated with using high doses of chemo-drugs in cancer treatment. This review focuses on emerging strategies to enhance the sensitization of tumor cells toward cancer therapies based on our understanding of tumor cell biology and underlying signaling pathways.
  3. 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).
  4. Park J, Choi JY, Choi J, Chung S, Song N, Park SK, et al.
    Cancers (Basel), 2021 May 14;13(10).
    PMID: 34069208 DOI: 10.3390/cancers13102370
    In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10-3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10-4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
  5. 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.

  6. Kramer I, Hooning MJ, Mavaddat N, Hauptmann M, Keeman R, Steyerberg EW, et al.
    Am J Hum Genet, 2020 11 05;107(5):837-848.
    PMID: 33022221 DOI: 10.1016/j.ajhg.2020.09.001
    Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
  7. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2020 Sep 04;125(10):102001.
    PMID: 32955327 DOI: 10.1103/PhysRevLett.125.102001
    The first study of charm quark diffusion with respect to the jet axis in heavy ion collisions is presented. The measurement is performed using jets with p_{T}^{jet}>60  GeV/c and D^{0} mesons with p_{T}^{D}>4  GeV/c in lead-lead (Pb-Pb) and proton-proton (pp) collisions at a nucleon-nucleon center-of-mass energy of sqrt[s_{NN}]=5.02  TeV, recorded by the CMS detector at the LHC. The radial distribution of D^{0} mesons with respect to the jet axis is sensitive to the production mechanisms of the meson, as well as to the energy loss and diffusion processes undergone by its parent parton inside the strongly interacting medium produced in Pb-Pb collisions. When compared to Monte Carlo event generators, the radial distribution in pp collisions is found to be well described by pythia, while the slope of the distribution predicted by sherpa is steeper than that of the data. In Pb-Pb collisions, compared to the pp results, the D^{0} meson distribution for 4
  8. Zhang H, Ahearn TU, Lecarpentier J, Barnes D, Beesley J, Qi G, et al.
    Nat Genet, 2020 06;52(6):572-581.
    PMID: 32424353 DOI: 10.1038/s41588-020-0609-2
    Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P 
  9. 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.
  10. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    PMID: 31976986 DOI: 10.1140/epjc/s10052-019-7499-4
    New sets of CMS underlying-event parameters ("tunes") are presented for the pythia8 event generator. These tunes use the NNPDF3.1 parton distribution functions (PDFs) at leading (LO), next-to-leading (NLO), or next-to-next-to-leading (NNLO) orders in perturbative quantum chromodynamics, and the strong coupling evolution at LO or NLO. Measurements of charged-particle multiplicity and transverse momentum densities at various hadron collision energies are fit simultaneously to determine the parameters of the tunes. Comparisons of the predictions of the new tunes are provided for observables sensitive to the event shapes at LEP, global underlying event, soft multiparton interactions, and double-parton scattering contributions. In addition, comparisons are made for observables measured in various specific processes, such as multijet, Drell-Yan, and top quark-antiquark pair production including jet substructure observables. The simulation of the underlying event provided by the new tunes is interfaced to a higher-order matrix-element calculation. For the first time, predictions from pythia8 obtained with tunes based on NLO or NNLO PDFs are shown to reliably describe minimum-bias and underlying-event data with a similar level of agreement to predictions from tunes using LO PDF sets.
  11. Li A, Geyer FC, Blecua P, Lee JY, Selenica P, Brown DN, et al.
    NPJ Breast Cancer, 2019 11 19;5:44.
    PMID: 31754629 DOI: 10.1038/s41523-019-0140-8
    [This corrects the article DOI: 10.1038/s41523-019-0115-9.].
  12. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2019 Jul 12;123(2):022001.
    PMID: 31386524 DOI: 10.1103/PhysRevLett.123.022001
    The transverse momentum spectra of D^{0} mesons from b hadron decays are measured at midrapidity (|y|<1) in pp and Pb-Pb collisions at a nucleon-nucleon center of mass energy of 5.02 TeV with the CMS detector at the LHC. The D^{0} mesons from b hadron decays are distinguished from prompt D^{0} mesons by their decay topologies. In Pb-Pb collisions, the B→D^{0} yield is found to be suppressed in the measured p_{T} range from 2 to 100  GeV/c as compared to pp collisions. The suppression is weaker than that of prompt D^{0} mesons and charged hadrons for p_{T} around 10  GeV/c. While theoretical calculations incorporating partonic energy loss in the quark-gluon plasma can successfully describe the measured B→D^{0} suppression at higher p_{T}, the data show an indication of larger suppression than the model predictions in the range of 2
  13. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2019 Apr 19;122(15):152001.
    PMID: 31050516 DOI: 10.1103/PhysRevLett.122.152001
    The modification of jet shapes in Pb-Pb collisions, relative to those in pp collisions, is studied for jets associated with an isolated photon. The data were collected with the CMS detector at the LHC at a nucleon-nucleon center-of-mass energy of 5.02 TeV. Jet shapes are constructed from charged particles with track transverse momenta (p_{T}) above 1  GeV/c in annuli around the axes of jets with p_{T}^{jet}>30  GeV/c associated with an isolated photon with p_{T}^{γ}>60  GeV/c. The jet shape distributions are consistent between peripheral Pb-Pb and pp collisions, but are modified for more central Pb-Pb collisions. In these central Pb-Pb events, a larger fraction of the jet momentum is observed at larger distances from the jet axis compared to pp, reflecting the interaction between the partonic medium created in heavy ion collisions and the traversing partons.
  14. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2019 Mar 29;122(12):121803.
    PMID: 30978057 DOI: 10.1103/PhysRevLett.122.121803
    This Letter describes a search for Higgs boson pair production using the combined results from four final states: bbγγ, bbττ, bbbb, and bbVV, where V represents a W or Z boson. The search is performed using data collected in 2016 by the CMS experiment from LHC proton-proton collisions at sqrt[s]=13  TeV, corresponding to an integrated luminosity of 35.9  fb^{-1}. Limits are set on the Higgs boson pair production cross section. A 95% confidence level observed (expected) upper limit on the nonresonant production cross section is set at 22.2 (12.8) times the standard model value. A search for narrow resonances decaying to Higgs boson pairs is also performed in the mass range 250-3000 GeV. No evidence for a signal is observed, and upper limits are set on the resonance production cross section.
  15. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2019 Mar 01;122(8):081804.
    PMID: 30932612 DOI: 10.1103/PhysRevLett.122.081804
    A search for heavy, narrow resonances decaying to a Higgs boson and a photon (Hγ) has been performed in proton-proton collision data at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9  fb^{-1} collected with the CMS detector at the LHC in 2016. Events containing a photon and a Lorentz-boosted hadronically decaying Higgs boson reconstructed as a single, large-radius jet are considered, and the γ+jet invariant mass spectrum is analyzed for the presence of narrow resonances. To increase the sensitivity of the search, events are categorized depending on whether or not the large-radius jet can be identified as a result of the merging of two jets originating from b quarks. Results in both categories are found to agree with the predictions of the standard model. Upper limits on the production rate of Hγ resonances are set as a function of their mass in the range of 720-3250 GeV, representing the most stringent constraints to date.
  16. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2019 Jan 18;122(2):021801.
    PMID: 30720313 DOI: 10.1103/PhysRevLett.122.021801
    A search for the Higgs boson decaying to two oppositely charged muons is presented using data recorded by the CMS experiment at the CERN LHC in 2016 at a center-of-mass energy sqrt[s]=13  TeV, corresponding to an integrated luminosity of 35.9  fb^{-1}. Data are found to be compatible with the predicted background. For a Higgs boson with a mass of 125.09 GeV, the 95% confidence level observed (background-only expected) upper limit on the production cross section times the branching fraction to a pair of muons is found to be 3.0 (2.5) times the standard model expectation. In combination with data recorded at center-of-mass energies sqrt[s]=7 and 8 TeV, the background-only expected upper limit improves to 2.2 times the standard model value with a standard model expected significance of 1.0 standard deviation. The corresponding observed upper limit is 2.9 with an observed significance of 0.9 standard deviation. This corresponds to an observed upper limit on the standard model Higgs boson branching fraction to muons of 6.4×10^{-4} and to an observed signal strength of 1.0±1.0(stat)±0.1(syst).
  17. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2019 Jan 11;122(1):011803.
    PMID: 31012697 DOI: 10.1103/PhysRevLett.122.011803
    A search is performed for dark matter particles produced in association with a top quark pair in proton-proton collisions at sqrt[s]=13  TeV. The data correspond to an integrated luminosity of 35.9  fb^{-1} recorded by the CMS detector at the LHC. No significant excess over the standard model expectation is observed. The results are interpreted using simplified models of dark matter production via spin-0 mediators that couple to dark matter particles and to standard model quarks, providing constraints on the coupling strength between the mediator and the quarks. These are the most stringent collider limits to date for scalar mediators, and the most stringent for pseudoscalar mediators at low masses.
  18. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Eur Phys J C Part Fields, 2019;79(2):90.
    PMID: 30814908 DOI: 10.1140/epjc/s10052-019-6556-3
    A search is presented for the single production of vector-like quarks in proton-proton collisions at


    s

    =
    13

    TeV

    . The data, corresponding to an integrated luminosity of 35.9



    fb

    -
    1



    , were recorded with the CMS experiment at the LHC. The analysis focuses on the vector-like quark decay into a top quark and a
    W
    boson, with one muon or electron in the final state. The mass of the vector-like quark candidate is reconstructed from hadronic jets, the lepton, and the missing transverse momentum. Methods for the identification of
    b
    quarks and of highly Lorentz boosted hadronically decaying top quarks and
    W
    bosons are exploited in this search. No significant deviation from the standard model background expectation is observed. Exclusion limits at 95% confidence level are set on the product of the production cross section and branching fraction as a function of the vector-like quark mass, which range from 0.3 to 0.03


    pb

    for vector-like quark masses of 700 to 2000


    GeV

    . Mass exclusion limits up to 1660


    GeV

    are obtained, depending on the vector-like quark type, coupling, and decay width. These represent the most stringent exclusion limits for the single production of vector-like quarks in this channel.
  19. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Eur Phys J C Part Fields, 2019;79(9):773.
    PMID: 31713548 DOI: 10.1140/epjc/s10052-019-7276-4
    A measurement for inclusive 2- and 3-jet events of the azimuthal correlation between the two jets with the largest transverse momenta, Δ ϕ 12 , is presented. The measurement considers events where the two leading jets are nearly collinear ("back-to-back") in the transverse plane and is performed for several ranges of the leading jet transverse momentum. Proton-proton collision data collected with the CMS experiment at a center-of-mass energy of 13 Te and corresponding to an integrated luminosity of 35.9 fb - 1 are used. Predictions based on calculations using matrix elements at leading-order and next-to-leading-order accuracy in perturbative quantum chromodynamics supplemented with leading-log parton showers and hadronization are generally in agreement with the measurements. Discrepancies between the measurement and theoretical predictions are as large as 15%, mainly in the region 177 ∘ < Δ ϕ 12 < 180 ∘ . The 2- and 3-jet measurements are not simultaneously described by any of models.
  20. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Eur Phys J C Part Fields, 2019;79(7):564.
    PMID: 31397444 DOI: 10.1140/epjc/s10052-019-7058-z
    A search is presented for a heavy pseudoscalar boson A decaying to a Z  boson and a Higgs boson with mass of 125 GeV . In the final state considered, the Higgs boson decays to a bottom quark and antiquark, and the Z  boson decays either into a pair of electrons, muons, or neutrinos. The analysis is performed using a data sample corresponding to an integrated luminosity of 35.9 fb - 1 collected in 2016 by the CMS experiment at the LHC from proton-proton collisions at a center-of-mass energy of 13 Te . The data are found to be consistent with the background expectations. Exclusion limits are set in the context of two-Higgs-doublet models in the A boson mass range between 225 and 1000 GeV .
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