Identification of Genes with Rare Loss of Function Variants Associated with Aggressive Prostate Cancer and Survival.

BACKGROUND: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes. OBJECTIVE: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS). DESIGN, SETTING, AND PARTICIPANTS: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival. RESULTS AND LIMITATIONS: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10-16) than noncarriers. CONCLUSIONS: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations. PATIENT SUMMARY: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Background Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. Methods We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. Results Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. Conclusions Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application

Measurement of inclusive D*+- and associated dijet cross sections in photoproduction at HERA

Inclusive photoproduction of D*+- mesons has been measured for photon-proton centre-of-mass energies in the range 130 < W < 280 GeV and a photon virtuality Q^2 < 1 GeV^2. The data sample used corresponds to an integrated luminosity of 37 pb^-1. Total and differential cross sections as functions of the D* transverse momentum and pseudorapidity are presented in restricted kinematical regions and the data are compared with next-to-leading order (NLO) perturbative QCD calculations using the "massive charm" and "massless charm" schemes. The measured cross sections are generally above the NLO calculations, in particular in the forward (proton) direction. The large data sample also allows the study of dijet production associated with charm. A significant resolved as well as a direct photon component contribute to the cross section. Leading order QCD Monte Carlo calculations indicate that the resolved contribution arises from a significant charm component in the photon. A massive charm NLO parton level calculation yields lower cross sections compared to the measured results in a kinematic region where the resolved photon contribution is significant.Comment: 32 pages including 6 figure

Observation of two new Ξb−\Xi_b^- baryon resonances

Two structures are observed close to the kinematic threshold in the $\Xi_b^0 \pi^-$ mass spectrum in a sample of proton-proton collision data, corresponding to an integrated luminosity of 3.0 fb$^{-1}$ recorded by the LHCb experiment. In the quark model, two baryonic resonances with quark content $bds$ are expected in this mass region: the spin-parity $J^P = \frac{1}{2}^+$ and $J^P=\frac{3}{2}^+$ states, denoted $\Xi_b^{\prime -}$ and $\Xi_b^{*-}$. Interpreting the structures as these resonances, we measure the mass differences and the width of the heavier state to be $m(\Xi_b^{\prime -}) - m(\Xi_b^0) - m(\pi^{-}) = 3.653 \pm 0.018 \pm 0.006$ MeV$/c^2$, $m(\Xi_b^{*-}) - m(\Xi_b^0) - m(\pi^{-}) = 23.96 \pm 0.12 \pm 0.06$ MeV$/c^2$, $\Gamma(\Xi_b^{*-}) = 1.65 \pm 0.31 \pm 0.10$ MeV, where the first and second uncertainties are statistical and systematic, respectively. The width of the lighter state is consistent with zero, and we place an upper limit of $\Gamma(\Xi_b^{\prime -}) < 0.08$ MeV at 95% confidence level. Relative production rates of these states are also reported.Comment: 17 pages, 2 figure

Measurement of the diffractive structure function in deep inelastic scattering at HERA

This paper presents an analysis of the inclusive properties of diffractive deep inelastic scattering events produced in $ep$ interactions at HERA. The events are characterised by a rapidity gap between the outgoing proton system and the remaining hadronic system. Inclusive distributions are presented and compared with Monte Carlo models for diffractive processes. The data are consistent with models where the pomeron structure function has a hard and a soft contribution. The diffractive structure function is measured as a function of \xpom, the momentum fraction lost by the proton, of $\beta$, the momentum fraction of the struck quark with respect to \xpom, and of $Q^2$. The \xpom dependence is consistent with the form \xpoma where $a~=~1.30~\pm~0.08~(stat)~^{+~0.08}_{-~0.14}~(sys)$ in all bins of $\beta$ and $Q^2$. In the measured $Q^2$ range, the diffractive structure function approximately scales with $Q^2$ at fixed $\beta$. In an Ingelman-Schlein type model, where commonly used pomeron flux factor normalisations are assumed, it is found that the quarks within the pomeron do not saturate the momentum sum rule.Comment: 36 pages, latex, 11 figures appended as uuencoded fil

Observation of J/ψpJ/\psi p resonances consistent with pentaquark states in Λb0→J/ψK−p{\Lambda_b^0\to J/\psi K^-p} decays

Observations of exotic structures in the $J/\psi p$ channel, that we refer to as pentaquark-charmonium states, in $\Lambda_b^0\to J/\psi K^- p$ decays are presented. The data sample corresponds to an integrated luminosity of 3/fb acquired with the LHCb detector from 7 and 8 TeV pp collisions. An amplitude analysis is performed on the three-body final-state that reproduces the two-body mass and angular distributions. To obtain a satisfactory fit of the structures seen in the $J/\psi p$ mass spectrum, it is necessary to include two Breit-Wigner amplitudes that each describe a resonant state. The significance of each of these resonances is more than 9 standard deviations. One has a mass of $4380\pm 8\pm 29$ MeV and a width of $205\pm 18\pm 86$ MeV, while the second is narrower, with a mass of $4449.8\pm 1.7\pm 2.5$ MeV and a width of $39\pm 5\pm 19$ MeV. The preferred $J^P$ assignments are of opposite parity, with one state having spin 3/2 and the other 5/2.Comment: 48 pages, 18 figures including the supplementary material, v2 after referee's comments, now 19 figure

Constraints on the unitarity triangle angle γ\gamma from Dalitz plot analysis of B0→DK+π−B^0 \to D K^+ \pi^- decays

The first study is presented of CP violation with an amplitude analysis of the Dalitz plot of $B^0 \to D K^+ \pi^-$ decays, with $D \to K^+ \pi^-$, $K^+ K^-$ and $\pi^+ \pi^-$. The analysis is based on a data sample corresponding to $3.0\,{\rm fb}^{-1}$ of $pp$ collisions collected with the LHCb detector. No significant CP violation effect is seen, and constraints are placed on the angle $\gamma$ of the unitarity triangle formed from elements of the Cabibbo-Kobayashi-Maskawa quark mixing matrix. Hadronic parameters associated with the $B^0 \to D K^*(892)^0$ decay are determined for the first time. These measurements can be used to improve the sensitivity to $\gamma$ of existing and future studies of the $B^0 \to D K^*(892)^0$ decay.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-059.html; updated to correct figure 9 (numerical results unchanged

Search for hidden-sector bosons in B0 ⁣→K∗0μ+μ−B^0 \!\to K^{*0}\mu^+\mu^- decays

A search is presented for hidden-sector bosons, $\chi$, produced in the decay ${B^0\!\to K^*(892)^0\chi}$, with $K^*(892)^0\!\to K^{+}\pi^{-}$ and $\chi\!\to\mu^+\mu^-$. The search is performed using $pp$-collision data corresponding to 3.0 fb$^{-1}$ collected with the LHCb detector. No significant signal is observed in the accessible mass range $214 \leq m({\chi}) \leq 4350$ MeV, and upper limits are placed on the branching fraction product $\mathcal{B}(B^0\!\to K^*(892)^0\chi)\times\mathcal{B}(\chi\!\to\mu^+\mu^-)$ as a function of the mass and lifetime of the $\chi$ boson. These limits are of the order of $10^{-9}$ for $\chi$ lifetimes less than 100 ps over most of the $m(\chi)$ range, and place the most stringent constraints to date on many theories that predict the existence of additional low-mass bosons.Comment: All figures and tables, along with supplementary material, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-036.htm

Measurement of the branching fraction ratio B(Bc+→ψ(2S)π+)/B(Bc+→J/ψπ+)\mathcal{B}(B_c^+ \rightarrow \psi(2S)\pi^+)/\mathcal{B}(B_c^+ \rightarrow J/\psi \pi^+)

Using $pp$ collision data collected by LHCb at center-of-mass energies $\sqrt{s}$ = 7 TeV and 8 TeV, corresponding to an integrated luminosity of 3 fb$^{-1}$, the ratio of the branching fraction of the $B_c^+ \rightarrow \psi(2S)\pi^+$ decay relative to that of the $B_c^+ \rightarrow J/\psi\pi^+$ decay is measured to be 0.268 $\pm$ 0.032 (stat) $\pm$ 0.007 (syst) $\pm$ 0.006 (BF). The first uncertainty is statistical, the second is systematic, and the third is due to the uncertainties on the branching fractions of the $J/\psi \rightarrow \mu^+\mu^-$ and $\psi(2S) \rightarrow \mu^+\mu^-$ decays. This measurement is consistent with the previous LHCb result, and the statistical uncertainty is halved.Comment: 17 pages including author list, 2 figure