Displaying publications 1 - 20 of 178 in total

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  1. Fulltext A Deep Neural Network for Simultaneous Estimation of b Jet Energy and Resolution
    Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Bergauer T, Dragicevic M, et al.
    Comput Softw Big Sci, 2020;4(1):10.
    PMID: 33196702 DOI: 10.1007/s41781-020-00041-z
    We describe a method to obtain point and dispersion estimates for the energies of jets arising from b quarks produced in proton-proton collisions at an energy of s = 13 TeV at the CERN LHC. The algorithm is trained on a large sample of simulated b jets and validated on data recorded by the CMS detector in 2017 corresponding to an integrated luminosity of 41 fb - 1 . A multivariate regression algorithm based on a deep feed-forward neural network employs jet composition and shape information, and the properties of reconstructed secondary vertices associated with the jet. The results of the algorithm are used to improve the sensitivity of analyses that make use of b jets in the final state, such as the observation of Higgs boson decay to b b ¯ .
  2. Fulltext A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk
    Lu Y, Beeghly-Fadiel A, Wu L, Guo X, Li B, Schildkraut JM, et al.
    Cancer Res, 2018 Sep 15;78(18):5419-5430.
    PMID: 30054336 DOI: 10.1158/0008-5472.CAN-18-0951
    Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.
  3. Fulltext A multi-dimensional search for new heavy resonances decaying to boosted W W , W Z , or Z Z boson pairs in the dijet final state at 13  Te
    Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Bergauer T, Brandstetter J, et al.
    Eur Phys J C Part Fields, 2020;80(3):237.
    PMID: 32215380 DOI: 10.1140/epjc/s10052-020-7773-5
    A search in an all-jet final state for new massive resonances decaying to W W , W Z , or Z Z boson pairs using a novel analysis method is presented. The analysis is performed on data corresponding to an integrated luminosity of 77.3 fb - 1 recorded with the CMS experiment at the LHC at a centre-of-mass energy of 13  Te . The search is focussed on potential narrow-width resonances with masses above 1.2  Te , where the decay products of each W or Z boson are expected to be collimated into a single, large-radius jet. The signal is extracted using a three-dimensional maximum likelihood fit of the two jet masses and the dijet invariant mass, yielding an improvement in sensitivity of up to 30% relative to previous search methods. No excess is observed above the estimated standard model background. In a heavy vector triplet model, spin-1 Z ' and W ' resonances with masses below 3.5 and 3.8   Te , respectively, are excluded at 95% confidence level. In a bulk graviton model, upper limits on cross sections are set between 27 and 0.2 fb for resonance masses between 1.2 and 5.2   Te , respectively. The limits presented in this paper are the best to date in the dijet final state.
  4. A search for decays of the Higgs boson to invisible particles in events with a top-antitop quark pair or a vector boson in proton-proton collisions at s=13TeV
    Tumasyan A, Adam W, Andrejkovic JW, Bergauer T, Chatterjee S, Damanakis K, et al.
    Eur Phys J C Part Fields, 2023;83(10):933.
    PMID: 37855556 DOI: 10.1140/epjc/s10052-023-11952-7
    A search for decays to invisible particles of Higgs bosons produced in association with a top-antitop quark pair or a vector boson, which both decay to a fully hadronic final state, has been performed using proton-proton collision data collected at s=13TeV by the CMS experiment at the LHC, corresponding to an integrated luminosity of 138fb-1. The 95% confidence level upper limit set on the branching fraction of the 125GeV Higgs boson to invisible particles, B(H→inv), is 0.54 (0.39 expected), assuming standard model production cross sections. The results of this analysis are combined with previous B(H→inv) searches carried out at s=7, 8, and 13TeV in complementary production modes. The combined upper limit at 95% confidence level on B(H→inv) is 0.15 (0.08 expected).
  5. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
    Mueller SH, Lai AG, Valkovskaya M, Michailidou K, Bolla MK, Wang Q, et al.
    Genome Med, 2023 Jan 26;15(1):7.
    PMID: 36703164 DOI: 10.1186/s13073-022-01152-5
    BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.

    METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.

    RESULTS: In European ancestry samples, 14 genes were significantly associated (q 

  6. Fulltext An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression
    Wyszynski A, Hong CC, Lam K, Michailidou K, Lytle C, Yao S, et al.
    Hum Mol Genet, 2016 Sep 01;25(17):3863-3876.
    PMID: 27402876 DOI: 10.1093/hmg/ddw223
    Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15 - 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.
  7. 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 
  8. Fulltext Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness
    Patel VL, Busch EL, Friebel TM, Cronin A, Leslie G, McGuffog L, et al.
    Cancer Res, 2020 Feb 01;80(3):624-638.
    PMID: 31723001 DOI: 10.1158/0008-5472.CAN-19-1840
    Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
  9. Fulltext Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3
    Hamdi Y, Soucy P, Kuchenbaeker KB, Pastinen T, Droit A, Lemaçon A, et al.
    Breast Cancer Res Treat, 2017 01;161(1):117-134.
    PMID: 27796716 DOI: 10.1007/s10549-016-4018-2
    PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.

    METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.

    RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.

    CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

  10. Fulltext Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer
    Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, McGuffog L, et al.
    JAMA, 2015 Apr 07;313(13):1347-61.
    PMID: 25849179 DOI: 10.1001/jama.2014.5985
    IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.

    OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2.

    DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.

    EXPOSURES: Mutations of BRCA1 or BRCA2.

    MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks.

    RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.

    CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

  11. Fulltext Author Correction: Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk
    Wilcox N, Dumont M, González-Neira A, Carvalho S, Joly Beauparlant C, Crotti M, et al.
    Nat Genet, 2023 Nov;55(11):2009.
    PMID: 37752376 DOI: 10.1038/s41588-023-01549-x
  12. Azimuthal Correlations within Exclusive Dijets with Large Momentum Transfer in Photon-Lead Collisions
    Tumasyan A, Adam W, Bergauer T, Dragicevic M, Del Valle AE, Frühwirth R, et al.
    Phys Rev Lett, 2023 Aug 04;131(5):051901.
    PMID: 37595238 DOI: 10.1103/PhysRevLett.131.051901
    The structure of nucleons is multidimensional and depends on the transverse momenta, spatial geometry, and polarization of the constituent partons. Such a structure can be studied using high-energy photons produced in ultraperipheral heavy-ion collisions. The first measurement of the azimuthal angular correlations of exclusively produced events with two jets in photon-lead interactions at large momentum transfer is presented, a process that is considered to be sensitive to the underlying nuclear gluon polarization. This study uses a data sample of ultraperipheral lead-lead collisions at sqrt[s_{NN}]=5.02  TeV, corresponding to an integrated luminosity of 0.38  nb^{-1}, collected with the CMS experiment at the LHC. The measured second harmonic of the correlation between the sum and difference of the two jet transverse momentum vectors is found to be positive, and rising, as the dijet transverse momentum increases. A well-tuned model that has been successful at describing a wide range of proton scattering data from the HERA experiments fails to describe the observed correlations, suggesting the presence of gluon polarization effects.
  13. Azimuthal correlations in Z +jets events in proton-proton collisions at s=13TeV
    Tumasyan A, Adam W, Andrejkovic JW, Bergauer T, Chatterjee S, Damanakis K, et al.
    Eur Phys J C Part Fields, 2023;83(8):722.
    PMID: 37578844 DOI: 10.1140/epjc/s10052-023-11833-z
    The production of Z bosons associated with jets is measured in pp collisions at s=13TeV with data recorded with the CMS experiment at the LHC corresponding to an integrated luminosity of 36.3fb-1. The multiplicity of jets with transverse momentum pT>30GeV is measured for different regions of the Z boson's pT(Z), from lower than 10GeV to higher than 100GeV. The azimuthal correlation Δϕ between the Z boson and the leading jet, as well as the correlations between the two leading jets are measured in three regions of pT(Z). The measurements are compared with several predictions at leading and next-to-leading orders, interfaced with parton showers. Predictions based on transverse-momentum dependent parton distributions and corresponding parton showers give a good description of the measurement in the regions where multiple parton interactions and higher jet multiplicities are not important. The effects of multiple parton interactions are shown to be important to correctly describe the measured spectra in the low pT(Z) regions.
  14. Fulltext BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer
    Shimelis H, Mesman RLS, Von Nicolai C, Ehlen A, Guidugli L, Martin C, et al.
    Cancer Res, 2017 Jun 01;77(11):2789-2799.
    PMID: 28283652 DOI: 10.1158/0008-5472.CAN-16-2568
    Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.
  15. Fulltext Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk
    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.
  16. Fulltext Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women
    Breast Cancer Association Consortium, Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, et al.
    N Engl J Med, 2021 02 04;384(5):428-439.
    PMID: 33471991 DOI: 10.1056/NEJMoa1913948
    BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.

    METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.

    RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.

    CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).

  17. Fulltext Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170
    Dunning AM, Michailidou K, Kuchenbaecker KB, Thompson D, French JD, Beesley J, et al.
    Nat Genet, 2016 Apr;48(4):374-86.
    PMID: 26928228 DOI: 10.1038/ng.3521
    We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) 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(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) 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.
  18. Fulltext CMS pythia  8 colour reconnection tunes based on underlying-event data
    Tumasyan A, Adam W, Andrejkovic JW, Bergauer T, Chatterjee S, Damanakis K, et al.
    Eur Phys J C Part Fields, 2023;83(7):587.
    PMID: 37440247 DOI: 10.1140/epjc/s10052-023-11630-8
    New sets of parameter tunes for two of the colour reconnection models, quantum chromodynamics-inspired and gluon-move, implemented in the pythia  8 event generator, are obtained based on the default CMS pythia  8 underlying-event tune, CP5. Measurements sensitive to the underlying event performed by the CMS experiment at centre-of-mass energies s=7 and 13TeV, and by the CDF experiment at 1.96TeV are used to constrain the parameters of colour reconnection models and multiple-parton interactions simultaneously. The new colour reconnection tunes are compared with various measurements at 1.96, 7, 8, and 13TeV including measurements of the underlying-event, strange-particle multiplicities, jet substructure observables, jet shapes, and colour flow in top quark pair (tt¯) events. The new tunes are also used to estimate the uncertainty related to colour reconnection modelling in the top quark mass measurement using the decay products of tt¯ events in the semileptonic channel at 13TeV.
  19. Fulltext Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)
    Silvestri V, Leslie G, Barnes DR, CIMBA Group, Agnarsson BA, Aittomäki K, et al.
    JAMA Oncol, 2020 Aug 01;6(8):1218-1230.
    PMID: 32614418 DOI: 10.1001/jamaoncol.2020.2134
    IMPORTANCE: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.

    OBJECTIVE: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.

    DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.

    MAIN OUTCOMES AND MEASURES: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.

    RESULTS: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P 

  20. Combination of Searches for Higgs Boson Pair Production in Proton-Proton Collisions at sqrt[s]=13  TeV
    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.
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