Optimized detection of homologous recombination deficiency improves the prediction of clinical outcomes in cancer

Peer reviewe

Heterogeneity and Clonal Evolution of Acquired PARP Inhibitor Resistance in TP53- and BRCA1-Deficient Cells

Homologous recombination (HR)-deficient cancers are sensitive to poly- ADP ribose polymerase inhibitors (PARPi), which have shown clinical efficacy in the treatment of high-grade serous cancers (HGSC). However, the majority of patients will relapse, and acquired PARPi resistance is emerging as a pressing clinical problem. Here we generated seven single-cell clones with acquired PARPi resistance derived from a PARPi-sensitive TP53(-/-) and BRCA1(-/-) epithelial cell line generated using CRISPR/Cas9. These clones showed diverse resistance mechanisms, and some clones presented with multiple mechanisms of resistance at the same time. Genomic analysis of the clones revealed unique transcriptional and mutational profiles and increased genomic instability in comparison with a PARPi-sensitive cell line. Clonal evolutionary analyses suggested that acquired PARPi resistance arose via clonal selection from an intrinsically unstable and heterogenous cell population in the sensitive cell line, which contained preexisting drug-tolerant cells. Similarly, clonal and spatial heterogeneity in tumor biopsies from a clinical patient with BRCA1-mutant HGSC with acquired PARPi resistance was observed. In an imaging-based drug screening, the clones showed heterogenous responses to targeted therapeutic agents, indicating that not all PARPi-resistant clones can be targeted with just one therapy. Furthermore, PARPi-resistant clones showed mechanism-dependent vulnerabilities to the selected agents, demonstrating that a deeper understanding on the mechanisms of resistance could lead to improved targeting and biomarkers for HGSC with acquired PARPi resistance. Significance: This study shows that BRCA1-deficient cells can give rise to multiple genomically and functionally heterogenous PARPi-resistant clones, which are associated with various vulnerabilities that can be targeted in a mechanism-specific manner.Peer reviewe

Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer

Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8+T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8+T-cells and PD-L1+macrophages and PD-L1+tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8+T-cells with PD-L1+macrophages in the first, and exhausted CD8+T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second. A Phase I/II trial previously revealed variable anti-tumor efficacy of the PARP inhibitor niraparib in combination with the PD-1 inhibitor pembrolizumab in platinum-resistant ovarian cancer patients. Here, the authors perform an integrated genomic and immunomics analysis of tumor samples from the same patients and find potential predictive biomarkers of response to such combination therapy.Peer reviewe

Search for physics beyond the standard model in events with two leptons, jets, and missing transverse momentum in pp collisions at √s = 8 TeV

A search is presented for physics beyond the standard model in final states with two opposite-sign same-flavor leptons, jets, and missing transverse momentum. The data sample corresponds to an integrated luminosity of 19.4 fb[superscript −1] of proton-proton collisions at √s = 8 TeV collected with the CMS detector at the CERN LHC in 2012. The analysis focuses on searches for a kinematic edge in the invariant mass distribution of the oppositesign same-flavor lepton pair and for final states with an on-shell Z boson. The observations are consistent with expectations from standard model processes and are interpreted in terms of upper limits on the production of supersymmetric particles.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Measurement of the W boson helicity in events with a single reconstructed top quark in pp collisions at √s = 8 TeV

A measurement of the W boson helicity is presented, where the W boson originates from the decay of a top quark produced in pp collisions. The event selection, optimized for reconstructing a single top quark in the final state, requires exactly one isolated lepton (muon or electron) and exactly two jets, one of which is likely to originate from the hadronization of a bottom quark. The analysis is performed using data recorded at a center-of-mass energy of 8 TeV with the CMS detector at the CERN LHC in 2012. The data sample corresponds to an integrated luminosity of 19.7 fb[superscript −1]. The measured helicity fractions are F [subscript L] = 0.298 ± 0.028 (stat) ± 0.032(syst), F [subscript 0] = 0.720 ± 0.039 (stat) ± 0.037(syst), and F [subscript R] = −0.018 ± 0.019 (stat) ± 0.011(syst). These results are used to set limits on the real part of the tWb anomalous couplings, g [subscript L] and g [subscript R]

Search for a standard model Higgs boson produced in association with a top-quark pair and decaying to bottom quarks using a matrix element method

A search for a standard model Higgs boson produced in association with a top-quark pair and decaying to bottom quarks is presented. Events with hadronic jets and one or two oppositely charged leptons are selected from a data sample corresponding to an integrated luminosity of 19.5 fb[superscript -1] collected by the CMS experiment at the LHC in pp collisions at a centre-of-mass energy of 8 TeV. In order to separate the signal from the larger t[bar over t] + jets background, this analysis uses a matrix element method that assigns a probability density value to each reconstructed event under signal or background hypotheses. The ratio between the two values is used in a maximum likelihood fit to extract the signal yield. The results are presented in terms of the measured signal strength modifier, μ, relative to the standard model prediction for a Higgs boson mass of 125 GeV. The observed (expected) exclusion limit at a 95 % confidence level is μ < 4.2 (3.3), corresponding to a best fit value [^ over μ] = 1.2[+1.6 over −1.5].United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Search for the production of dark matter in association with top-quark pairs in the single-lepton final state in proton-proton collisions at √s = 8 TeV

A search is presented for particle dark matter produced in association with a pair of top quarks in pp collisions at a centre-of-mass energy of √s = 8 TeV. The data were collected with the CMS detector at the LHC and correspond to an integrated luminosity of 19.7 fb[superscript −1]. This search requires the presence of one lepton, multiple jets, and large missing transverse energy. No excess of events is found above the SM expectation, and upper limits are derived on the production cross section. Interpreting the findings in the context of a scalar contact interaction between fermionic dark matter particles and top quarks, lower limits on the interaction scale are set. These limits are also interpreted in terms of the dark matter-nucleon scattering cross sections for the spin-independent scalar operator and they complement direct searches for dark matter particles in the low mass region.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Search for new physics in events with same-sign dileptons and jets in pp collisions at √s = 8 TeV

A search for new physics is performed based on events with jets and a pair of isolated, same-sign leptons. The results are obtained using a sample of proton-proton collision data collected by the CMS experiment at a centre-of-mass energy of 8 TeV at the LHC, corresponding to an integrated luminosity of 19.5 fb[superscript −1]. In order to be sensitive to a wide variety of possible signals beyond the standard model, multiple search regions defined by the missing transverse energy, the hadronic energy, the number of jets and b-quark jets, and the transverse momenta of the leptons in the events are considered. No excess above the standard model background expectation is observed and constraints are set on a number of models for new physics, as well as on the same-sign top-quark pair and quadruple-top-quark production cross sections. Information on event selection efficiencies is also provided, so that the results can be used to confront an even broader class of new physics models.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Search for the associated production of the Higgs boson with a top-quark pair

A search for the standard model Higgs boson produced in association with a top-quark pair (tt¯H) is presented, using data samples corresponding to integrated luminosities of up to 5.1 fb−1 and 19.7 fb−1 collected in pp collisions at center-of-mass energies of 7 TeV and 8 TeV respectively. The search is based on the following signatures of the Higgs boson decay: H → hadrons, H → photons, and H → leptons. The results are characterized by an observed tt¯H signal strength relative to the standard model cross section, μ=σ/σ SM,under the assumption that the Higgs boson decays as expected in the standard model. The best fit value is μ = 2.8 ± 1.0 for a Higgs boson mass of 125.6 GeV.National Science Foundation (U.S.

Search for new resonances decaying via WZ to leptons in proton–proton collisions at √s = 8 TeV

A search is performed in proton–proton collisions at √s = 8 TeV for exotic particles decaying via WZ to fully leptonic final states with electrons, muons, and neutrinos. The data set corresponds to an integrated luminosity of 19.5 fb[superscript −1]. No significant excess is observed above the expected standard model background. Upper bounds at 95% confidence level are set on the production cross section of a W′ boson as predicted by an extended gauge model, and on the W′WZ coupling. The expected and observed mass limits for a W′ boson, as predicted by this model, are 1.55 and 1.47 TeV, respectively. Stringent limits are also set in the context of low-scale technicolor models under a range of assumptions for the model parameters.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio