67 research outputs found
Recommended from our members
Exome and whole genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity
The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a five-year survival rate of 15%, identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole exome sequencing of 149 EAC tumors/normal pairs, 15 of which have also been subjected to whole genome sequencing. We identify a mutational signature defined by a high prevalence of A to C transversions at AA dinucleotides. Statistical analysis of exome data identified significantly mutated 26 genes. Of these genes, four (TP53, CDKN2A, SMAD4, and PIK3CA) have been previously implicated in EAC. The novel significantly mutated genes include chromatin modifying factors and candidate contributors: SPG20, TLR4, ELMO1, and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 reveal increased cellular invasion. Therefore, we suggest a new hypothesis about the potential activation of the RAC1 pathway to be a contributor to EAC tumorigenesis
Recommended from our members
Whole exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer
Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two prostate cancer patients including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early-trunk and 56 metastatic-trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic
Recommended from our members
The genetic landscape of high-risk neuroblastoma
Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%1. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of whole exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per megabase (0.48 non-silent), and remarkably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, an additional 7.1% had focal deletions), MYCN (1.7%, a recurrent p.Pro44Leu alteration), and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1, and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies reliant upon frequently altered oncogenic drivers
Medulloblastoma Exome Sequencing Uncovers Subtype-Specific Somatic Mutations
Medulloblastomas are the most common malignant brain tumors in children1. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles2–5. Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma
A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches
Critical Involvement of the ATM-Dependent DNA Damage Response in the Apoptotic Demise of HIV-1-Elicited Syncytia
DNA damage can activate the oncosuppressor protein ataxia telangiectasia mutated (ATM), which phosphorylates the histone H2AX within characteristic DNA damage foci. Here, we show that ATM undergoes an activating phosphorylation in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. This was accompanied by aggregation of ATM in discrete nuclear foci that also contained phospho-histone H2AX. DNA damage foci containing phosphorylated ATM and H2AX were detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Knockdown of ATM or of its obligate activating factor NBS1 (Nijmegen breakage syndrome 1 protein), as well as pharmacological inhibition of ATM with KU-55933, inhibited H2AX phosphorylation and prevented Env-elicited syncytia from undergoing apoptosis. ATM was found indispensable for the activation of MAP kinase p38, which catalyzes the activating phosphorylation of p53 on serine 46, thereby causing p53 dependent apoptosis. Both wild type HIV-1 and an HIV-1 mutant lacking integrase activity induced syncytial apoptosis, which could be suppressed by inhibiting ATM. HIV-1-infected T lymphoblasts from patients with inactivating ATM or NBS1 mutations also exhibited reduced syncytial apoptosis. Altogether these results indicate that apoptosis induced by a fusogenic HIV-1 Env follows a pro-apoptotic pathway involving the sequential activation of ATM, p38MAPK and p53
Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS
Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, “S-XL6,” was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A’s in vivo half-life; and that S-XL6 crosses the blood–brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS
Cosmology with the Laser Interferometer Space Antenna
254 pags:, 44 figs.The Laser Interferometer Space Antenna (LISA) has two scientific objectives of cosmological focus: to probe the expansion rate of the universe, and to understand stochastic gravitational-wave backgrounds and their implications for early universe and particle physics, from the MeV to the Planck scale. However, the range of potential cosmological applications of gravitational-wave observations extends well beyond these two objectives. This publication presents a summary of the state of the art in LISA cosmology, theory and methods, and identifies new opportunities to use gravitational-wave observations by LISA to probe the universe.This work is partly supported by: A.G. Leventis Foundation; Academy of Finland
Grants 328958 and 345070; Alexander S. Onassis Foundation, Scholarship ID: FZO 059-1/2018-2019;
Amaldi Research Center funded by the MIUR program “Dipartimento di Eccellenza” (CUP:
B81I18001170001); ASI Grants No. 2016-24-H.0 and No. 2016-24-H.1-2018; Atracción de Talento
Grant 2019-T1/TIC-15784; Atracción de Talento contract no. 2019-T1/TIC-13177 granted by the
Comunidad de Madrid; Ayuda ‘Beatriz Galindo Senior’ by the Spanish ‘Ministerio de Universidades’,
Grant BG20/00228; Basque Government Grant (IT-979-16); Belgian Francqui Foundation; Centre national
d’Etudes spatiales; Ben Gurion University Kreitman Fellowship, and the Israel Academy of Sciences and
Humanities (IASH) & Council for Higher Education (CHE) Excellence Fellowship Program for
International Postdoctoral Researchers; Centro de Excelencia Severo Ochoa Program SEV-2016-0597;
CERCA program of the Generalitat de Catalunya; Cluster of Excellence “Precision Physics, Fundamental
Interactions, and Structure of Matter” (PRISMA? EXC 2118/1); Comunidad de Madrid, Contrato de
Atracción de Talento 2017-T1/TIC-5520; Czech Science Foundation GAČR, Grant No. 21-16583M; Delta
ITP consortium; Department of Energy under Grant No. DE-SC0008541, DE-SC0009919 and DESC0019195; Deutsche Forschungsgemeinschaft (DFG), Project ID 438947057; Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy - EXC 2121 Quantum Universe - 390833306; European
Structural and Investment Funds and the Czech Ministry of Education, Youth and Sports (Project
CoGraDS - CZ.02.1.01/0.0/0.0/15 003/0000437); European Union’s H2020 ERC Consolidator Grant
“GRavity from Astrophysical to Microscopic Scales” (Grant No. GRAMS-815673); European Union’s
H2020 ERC, Starting Grant Agreement No. DarkGRA-757480; European Union’s Horizon 2020
programme under the Marie Sklodowska-Curie Grant Agreement 860881 (ITN HIDDeN); European
Union’s Horizon 2020 Research and Innovation Programme Grant No. 796961, “AxiBAU” (K.S.);
European Union’s Horizon 2020 Research Council grant 724659 MassiveCosmo ERC-2016-COG; FCT
through national funds (PTDC/FIS-PAR/31938/2017) and through project “BEYLA – BEYond LAmbda”
with Ref. Number PTDC/FIS-AST/0054/2021; FEDER-Fundo Europeu de Desenvolvimento Regional
through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI-01-0145-
FEDER-031938) and research Grants UIDB/04434/2020 and UIDP/04434/2020; Fondation CFM pour la
Recherche in France; Foundation for Education and European Culture in Greece; French ANR project
MMUniverse (ANR-19-CE31-0020); FRIA Grant No.1.E.070.19F of the Belgian Fund for Research, F.R.
S.-FNRS Fundação para a Ciência e a Tecnologia (FCT) through Contract No. DL 57/2016/CP1364/
CT0001; Fundação para a Ciência e a Tecnologia (FCT) through Grants UIDB/04434/2020, UIDP/04434/
2020, PTDC/FIS-OUT/29048/2017, CERN/FIS-PAR/0037/2019 and “CosmoTests – Cosmological tests of
gravity theories beyond General Relativity” CEECIND/00017/2018; Generalitat Valenciana Grant
PROMETEO/2021/083; Grant No. 758792, project GEODESI; Government of Canada through the
Department of Innovation, Science and Economic Development and Province of Ontario through the
Ministry of Colleges and Universities; Grants-in-Aid for JSPS Overseas Research Fellow (No.
201960698); I?D Grant PID2020-118159GB-C41 of the Spanish Ministry of Science and Innovation;
INFN iniziativa specifica TEONGRAV; Israel Science Foundation (Grant No. 2562/20); Japan Society for
the Promotion of Science (JSPS) KAKENHI Grant Nos. 20H01899 and 20H05853; IFT Centro de
Excelencia Severo Ochoa Grant SEV-2; Kavli Foundation and its founder Fred Kavli; Minerva
Foundation; Ministerio de Ciencia e Innovacion Grant PID2020-113644GB-I00; NASA Grant
80NSSC19K0318; NASA Hubble Fellowship grants No. HST-HF2-51452.001-A awarded by the Space
Telescope Science Institute with NASA contract NAS5-26555; Netherlands Organisation for Science and
Research (NWO) Grant Number 680-91-119; new faculty seed start-up grant of the Indian Institute of
Science, Bangalore, the Core Research Grant CRG/2018/002200 of the Science and Engineering; NSF
Grants PHY-1820675, PHY-2006645 and PHY-2011997; Polish National Science Center Grant 2018/31/D/
ST2/02048; Polish National Agency for Academic Exchange within the Polish Returns Programme under
Agreement PPN/PPO/2020/1/00013/U/00001; Pró-Reitoria de Pesquisa of Universidade Federal de Minas
Gerais (UFMG) under Grant No. 28359; Ramón y Cajal Fellowship contract RYC-2017-23493; Research
Project PGC2018-094773-B-C32 [MINECO-FEDER]; Research Project PGC2018-094773-B-C32
[MINECO-FEDER]; ROMFORSK Grant Project. No. 302640; Royal Society Grant URF/R1/180009
and ERC StG 949572: SHADE; Shota Rustaveli National Science Foundation (SRNSF) of Georgia (Grant
FR/18-1462); Simons Foundation/SFARI 560536; SNSF Ambizione grant; SNSF professorship Grant
(No. 170547); Spanish MINECO’s “Centro de Excelencia Severo Ochoa” Programme Grants SEV-2016-
0597 and PID2019-110058GB-C22; Spanish Ministry MCIU/AEI/FEDER Grant (PGC2018-094626-BC21); Spanish Ministry of Science and Innovation (PID2020-115845GB-I00/AEI/10.13039/
501100011033); Spanish Proyectos de I?D via Grant PGC2018-096646-A-I00; STFC Consolidated
Grant ST/T000732/1; STFC Consolidated Grants ST/P000762/1 and ST/T000791/1; STFC Grant ST/
S000550/1; STFC Grant ST/T000813/1; STFC Grants ST/P000762/1 and ST/T000791/1; STFC under the
research Grant ST/P000258/1; Swiss National Science Foundation (SNSF), project The Non-Gaussian
Universe and Cosmological Symmetries, Project Number: 200020-178787; Swiss National Science
Foundation Professorship Grants No. 170547 and No. 191957; SwissMap National Center for Competence
in Research; “The Dark Universe: A Synergic Multi-messenger Approach” Number 2017X7X85K under
the MIUR program PRIN 2017; UK Space Agency; UKSA Flagship Project, Euclid.Peer reviewe
The molecular logic of endocannabinoid signalling
The endocannabinoids are a family of lipid messengers that engage the cell surface receptors that are targeted by Δ9-tetrahydrocannabinol, the active principle in marijuana (Cannabis). They are made on demand through cleavage of membrane precursors and are involved in various short-range signalling processes. In the brain, they combine with CB1 cannabinoid receptors on axon terminals to regulate ion channel activity and neurotransmitter release. Their ability to modulate synaptic efficacy has a wide range of functional consequences and provides unique therapeutic possibilities. © 2003, Nature Publishing Group. All rights reserved
Neutral models for patchy landscapes
The landscapes currently studied in ecology are either “discontinuous” (category-based or patch-based), as in the case of mosaics of agricultural units, or of more “continuous” type (raster lattices), as used for representing elevation or other ecological gradients. The main landscape models either involve explicit processes or are neutral, recreating spatial patterns in the absence of studied processes (using statistical rules). This article presents neutral models suitable for the creation and handling of patchy landscapes. These models (Patchy Landscape Neutral Models) adapt the Gibbs process already used successfully in forestry and biology to describe the local interactions between landscape units. These interactions can be either ecological, if justified, for example, by natural mechanisms of dispersal (plant species dynamics), or crop successions in anthropized landscapes, or statistical (geometrical). We define a global “cost function” representative of the landscape to be simulated by summing the “pair function” that expresses the interactions between units for the whole landscape. This generic approach makes it possible to reconstruct different kinds of patchy landscape compositions (land cover) and opens the way to study changes in landscape configuration (unit arrangements) as well as an analytical description of landscape
- …