DOCSLIB.ORG

Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer Published OnlineFirst May 31, 2018; DOI: 10.1158/2159-8290.CD-18-0349 RESEARCH ARTICLE Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer Hervé Tiriac1, Pascal Belleau1, Dannielle D. Engle1, Dennis Plenker1, Astrid Deschênes1, Tim D. D. Somerville1, Fieke E. M. Froeling1, Richard A. Burkhart2, Robert E. Denroche3, Gun-Ho Jang3, Koji Miyabayashi1, C. Megan Young1,4, Hardik Patel1, Michelle Ma1, Joseph F. LaComb5, Randze Lerie D. Palmaira6, Ammar A. Javed2, Jasmine C. Huynh7, Molly Johnson8, Kanika Arora8, Nicolas Robine8, Minita Shah8, Rashesh Sanghvi8, Austin B. Goetz9, Cinthya Y. Lowder9, Laura Martello10, Else Driehuis11,12, Nicolas LeComte6, Gokce Askan6, Christine A. Iacobuzio-Donahue6, Hans Clevers11,12,13, Laura D. Wood14, Ralph H. Hruban14, Elizabeth Thompson14, Andrew J. Aguirre15, Brian M. Wolpin15, Aaron Sasson16, Joseph Kim16, Maoxin Wu17, Juan Carlos Bucobo5, Peter Allen6, Divyesh V. Sejpal18, William Nealon19, James D. Sullivan19, Jordan M. Winter9, Phyllis A. Gimotty20, Jean L. Grem21, Dominick J. DiMaio22, Jonathan M. Buscaglia5, Paul M. Grandgenett23, Jonathan R. Brody9, Michael A. Hollingsworth23, Grainne M. O’Kane24, Faiyaz Notta3, Edward Kim7, James M. Crawford25, Craig Devoe26, Allyson Ocean27, Christopher L. Wolfgang2, Kenneth H. Yu6, Ellen Li5, Christopher R. Vakoc1, Benjamin Hubert8, Sandra E. Fischer28,29, Julie M. Wilson3, Richard Moffitt16,30, Jennifer Knox24, Alexander Krasnitz1, Steven Gallinger3,24,31,32, and David A. Tuveson1 ABSTRACT Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient–derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver onco- genes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited hetero- geneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent thera- peutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. SIGNIFICANCE: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1–18. ©2018 AACR. 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. 2Johns Philadelphia, Pennsylvania. 10SUNY Downstate Medical Center, Depart- Hopkins University, Division of Hepatobiliary and Pancreatic Surgery, ment of Medicine, New York, New York. 11Hubrecht Institute, Royal Neth- Baltimore, Maryland. 3PanCuRx Translational Research Initiative, Ontario erlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands. Institute for Cancer Research, Toronto, Ontario, Canada. 4Swiss Fed- 12University Medical Center (UMC), Utrecht, the Netherlands. 13Princess eral Institute of Technology Lausanne (EPFL), School of Life Sciences, Maxime Center (PMC), Utrecht, the Netherlands. 14Department of Pathol- Swiss Institute for Experimental Cancer Research (ISREC), Laboratory ogy, Johns Hopkins University, Baltimore, Maryland. 15Dana-Farber Can- of Tumor Heterogeneity and Stemness in Cancer, Lausanne, Switzerland. cer Institute, Broad Institute, Boston, Massachusetts. 16Department of 5Department of Medicine, Stony Brook University, Stony Brook, New York. Surgery, Stony Brook University, Stony Brook, New York. 17Department 6Memorial Sloan Kettering Cancer Center, New York, New York. 7University of Pathology, Stony Brook University, Stony Brook, New York. 18Donald of California, Davis, Comprehensive Cancer Center, Division of Hematol- and Barbara Zucker School of Medicine at Hofstra/Northwell, Division ogy and Oncology, Sacramento, California. 8New York Genome Center, New of Gastroenterology, Hempstead, New York. 19Department of Surgery, York, New York. 9Department of Surgery, Thomas Jefferson University, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, OF1 | CANCER DISCOVERY SEPTEMBER 2018 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst May 31, 2018; DOI: 10.1158/2159-8290.CD-18-0349 Pancreatic Cancer Organoids Parallel Patient Response RESEARCH ARTICLE is used in conjunction with oncologic resection but adds INTRODUCTION only a modest benefit in survival (4, 5). Most patients are not Pancreatic ductal adenocarcinoma (PDAC) is a deadly surgical candidates and are diagnosed with locally advanced malignancy often diagnosed at advanced stages. Fifteen to or metastatic disease. Therapeutic options for these patients thirty percent of patients with PDAC are diagnosed with include the combination chemotherapy regimens gemcit- clinically localized disease that is amenable to potentially abine/nab-paclitaxel (6) or FOLFIRINOX (5-fluorouracil, curative surgical resection (1, 2). Following surgical resec- leucovorin, irinotecan, and oxaliplatin; ref. 7). Despite thera- tion, the majority of patients will have local or distant recur- peutic intervention, the median overall survival (OS) is 6.7 rence (3) and succumb to the disease. Systemic treatment, in to 11.1 months [progression-free survival (PFS) = 3.3–6.4] the form of neoadjuvant or adjuvant cytotoxic chemotherapy, for advanced disease (6, 7), compared with 25 to 28 months Hempstead, New York. 20Department of Biostatistics, Epidemiology and 30Department of Biomedical Informatics, Stony Brook University, Stony Informatics, University of Pennsylvania, Philadelphia, Pennsylvania. Brook, New York. 31Lunenfeld-Tanenbaum Research Institute, Mount 21Department of Medicine, University of Nebraska Medical Center, Omaha, Sinai Hospital, Toronto, Ontario, Canada. 32Hepatobiliary/Pancreatic Nebraska. 22Department of Pathology and Microbiology, University of Surgical Oncology Program, University Health Network, Toronto, Ontario, Nebraska Medical Center, Omaha, Nebraska. 23University of Nebraska Canada. Medical Center, Eppley Institute for Research in Cancer and Allied Dis- Note: Supplementary data for this article are available at Cancer Discovery eases, Fred & Pamela Buffet Cancer Center, Omaha, Nebraska. 24Wallace Online (http://cancerdiscovery.aacrjournals.org/). McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Univer- P. Belleau and D.D. Engle contributed equally to this article. 25 sity of Toronto, Toronto, Ontario, Canada. Department of Pathology and Corresponding Authors: David A. Tuveson, Cold Spring Harbor Laboratory, Laboratory Medicine, Donald and Barbara Zucker School of Medicine at 1 Bungtown Road, Cold Spring Harbor, NY 11724. Phone: 516-367-5246; 26 Hofstra/Northwell, Hempstead, New York. Division of Medical Oncology, Fax: 516-367-8353; E-mail: [email protected]; and Steven Gallinger, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Toronto General Hospital, 200 Elizabeth Street, 10EN, Room 206, Toronto, 27 Hempstead, New York. Weill Cornell Medical College, New York, New Ontario M5G 2C4, Canada. E-mail: [email protected] York. 28Department of Pathology, University Health Network, University doi: 10.1158/2159-8290.CD-18-0349 of Toronto, Toronto, Ontario, Canada. 29Department of Laboratory Medi- cine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. ©2018 American Association for Cancer Research. SEPTEMBER 2018 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst May 31, 2018; DOI: 10.1158/2159-8290.CD-18-0349 RESEARCH ARTICLE Tiriac et al. (PFS = 13.1–13.9) in surgically resected patients (4). Many tome, we identify the expected hallmarks of PDAC. In addi- patients with PDAC have chemorefractory disease, but a tion, we find high concordance between the primary tumor smaller subset exhibits significant response to chemotherapy. and paired PDO samples when sufficient neoplastic cellularity Current therapeutic selection for patients with both local was observed in the patient specimen. We establish a PDAC- and metastatic pancreatic cancer is often based on patient specific PDO drug-testing pipeline, termed “pharmacotyp- performance status and comorbidities. Altogether, this high- ing,” and demonstrate that drug-sensitivity profiles can be lights the unmet clinical need to define responsive subgroups generated for each PDO within a clinically meaningful time- to inform treatment selection and to nominate alternative frame. In a retrospective analysis of a small subset of patients treatment options for patients who are resistant
Load more

Recommended publications
  • WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US).
    [Show full text]
  • Supplementary Table S2
    1-high in cerebrotropic Gene P-value patients Definition BCHE 2.00E-04 1 Butyrylcholinesterase PLCB2 2.00E-04 -1 Phospholipase C, beta 2 SF3B1 2.00E-04 -1 Splicing factor 3b, subunit 1 BCHE 0.00022 1 Butyrylcholinesterase ZNF721 0.00028 -1 Zinc finger protein 721 GNAI1 0.00044 1 Guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 1 GNAI1 0.00049 1 Guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 1 PDE1B 0.00069 -1 Phosphodiesterase 1B, calmodulin-dependent MCOLN2 0.00085 -1 Mucolipin 2 PGCP 0.00116 1 Plasma glutamate carboxypeptidase TMX4 0.00116 1 Thioredoxin-related transmembrane protein 4 C10orf11 0.00142 1 Chromosome 10 open reading frame 11 TRIM14 0.00156 -1 Tripartite motif-containing 14 APOBEC3D 0.00173 -1 Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3D ANXA6 0.00185 -1 Annexin A6 NOS3 0.00209 -1 Nitric oxide synthase 3 SELI 0.00209 -1 Selenoprotein I NYNRIN 0.0023 -1 NYN domain and retroviral integrase containing ANKFY1 0.00253 -1 Ankyrin repeat and FYVE domain containing 1 APOBEC3F 0.00278 -1 Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3F EBI2 0.00278 -1 Epstein-Barr virus induced gene 2 ETHE1 0.00278 1 Ethylmalonic encephalopathy 1 PDE7A 0.00278 -1 Phosphodiesterase 7A HLA-DOA 0.00305 -1 Major histocompatibility complex, class II, DO alpha SOX13 0.00305 1 SRY (sex determining region Y)-box 13 ABHD2 3.34E-03 1 Abhydrolase domain containing 2 MOCS2 0.00334 1 Molybdenum cofactor synthesis 2 TTLL6 0.00365 -1 Tubulin tyrosine ligase-like family, member 6 SHANK3 0.00394 -1 SH3 and multiple ankyrin repeat domains 3 ADCY4 0.004 -1 Adenylate cyclase 4 CD3D 0.004 -1 CD3d molecule, delta (CD3-TCR complex) (CD3D), transcript variant 1, mRNA.
    [Show full text]
  • Literature Mining Sustains and Enhances Knowledge Discovery from Omic Studies
    LITERATURE MINING SUSTAINS AND ENHANCES KNOWLEDGE DISCOVERY FROM OMIC STUDIES by Rick Matthew Jordan B.S. Biology, University of Pittsburgh, 1996 M.S. Molecular Biology/Biotechnology, East Carolina University, 2001 M.S. Biomedical Informatics, University of Pittsburgh, 2005 Submitted to the Graduate Faculty of School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2016 UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Rick Matthew Jordan It was defended on December 2, 2015 and approved by Shyam Visweswaran, M.D., Ph.D., Associate Professor Rebecca Jacobson, M.D., M.S., Professor Songjian Lu, Ph.D., Assistant Professor Dissertation Advisor: Vanathi Gopalakrishnan, Ph.D., Associate Professor ii Copyright © by Rick Matthew Jordan 2016 iii LITERATURE MINING SUSTAINS AND ENHANCES KNOWLEDGE DISCOVERY FROM OMIC STUDIES Rick Matthew Jordan, M.S. University of Pittsburgh, 2016 Genomic, proteomic and other experimentally generated data from studies of biological systems aiming to discover disease biomarkers are currently analyzed without sufficient supporting evidence from the literature due to complexities associated with automated processing. Extracting prior knowledge about markers associated with biological sample types and disease states from the literature is tedious, and little research has been performed to understand how to use this knowledge to inform the generation of classification models from ‘omic’ data. Using pathway analysis methods to better understand the underlying biology of complex diseases such as breast and lung cancers is state-of-the-art. However, the problem of how to combine literature- mining evidence with pathway analysis evidence is an open problem in biomedical informatics research.
    [Show full text]
  • Systematic Analysis and Biomarker Study for Alzheimer's Disease
    Xinzhong Li, Haiyan Wang, Jintao Long, Genhua Pan, Taigang He, Oleg Anichtchi k, Robert Belshaw, Diego Albani , Paul Edison, Elaine K Green and James Scott Systematic analysis and biomarker study for Alzheimer’s disease Article (Published version) (Refereed) Original citation: Li, Xinzhong and Wang, Haiyan and Long, Jintao and Pan, Genhua and He, Taigang and Anichtchik, Oleg and Belshaw, Robert and Albani, Diego and Edison, Paul and Green, Elaine K. and Scott, James (2018) Systematic analysis and biomarker study for Alzheimer’s disease. Scientific Reports , 8 (17394). ISSN 2045-2322 DOI: https://doi.org/10.1038/s41598-018-35789-3 © 2018 Springer Nature Publishing AG CC -BY 4.0 This version available at: http://eprints.lse.ac.uk/id/eprint/91279 Available in LSE Research Online: December 2018 LSE has developed LSE Research Online so that users may access research output of the School. Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Users may download and/or print one copy of any article(s) in LSE Research Online to facilitate their private study or for non-commercial research. You may not engage in further distribution of the material or use it for any profit-making activities or any commercial gain. You may freely distribute the URL ( http://eprints.lse.ac.uk ) of the LSE Research Online website. ǤǤ Ȁ Systematic Analysis and Biomarker Study for Alzheimer’s Disease Xinzhong Li ͷ, Haiyan Wang͸, Jintao Longͷ, Genhua Pan͹, Taigang He ͺ, Oleg Anichtchikͷ, Robert Belshawͷ, Diego Albani ͻ, Paul Edisonͼ, Elaine K Greenͷ & James Scottͼ Received: 3 April 2018 Revealing the relationship between dysfunctional genes in blood and brain tissues from patients with Accepted: 28 October 2018 Alzheimer’s Disease (AD) will help us to understand the pathology of this disease.
    [Show full text]
  • Protein-Protein Interaction Network Alignment and Evolution
    Protein-Protein Interaction Network Alignment and Evolution by Brian Man-Kin Law A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Computer Science University of Toronto © Copyright by Brian Law 2019 Protein-Protein Interaction Network Alignment and Evolution Brian Law Doctor of Philosophy Computer Science University of Toronto 2019 Abstract Network alignment is an emerging analysis method enabled by the rapid large-scale collection of protein-protein interaction data for many different species. As sequence alignment did for gene evolution, network alignment will hopefully provide new insights into network evolution and serve as a new bioinformatic tool for making biological inferences across species. Using new SH3 binding data from Saccharomyces cerevisiae , Caenorhabditis elegans , and Homo sapiens , I construct new interface-interaction networks and devise a new network alignment method for these networks. With appropriate parameterization, this method is highly successful at generating alignments that reflect known protein orthology information and contain high network topology overlap. However, close examination of the optimal parameterization reveals a heavy reliance on protein sequence similarity and fungibility of other data features, including network topology data, an observation that may also pertain to protein-protein interaction network alignment. Closer examination of interactomic data, along with established orthology data, reveals that protein-protein interaction conservation is quite low across multiple species, suggesting that the high network topology overlap achieved by contemporary network aligners is ill-advised if biological relevance of results is desired. Further consideration of gene duplication and protein ii binding sites reveal additional PPI evolution phenomena further reducing the network topology overlap expected in network alignments, casting doubt on the utility of network alignment metrics solely based on network topology.
    [Show full text]
  • Nº Ref Uniprot Proteína Péptidos Identificados Por MS/MS 1 P01024
    Document downloaded from http://www.elsevier.es, day 26/09/2021. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Nº Ref Uniprot Proteína Péptidos identificados 1 P01024 CO3_HUMAN Complement C3 OS=Homo sapiens GN=C3 PE=1 SV=2 por 162MS/MS 2 P02751 FINC_HUMAN Fibronectin OS=Homo sapiens GN=FN1 PE=1 SV=4 131 3 P01023 A2MG_HUMAN Alpha-2-macroglobulin OS=Homo sapiens GN=A2M PE=1 SV=3 128 4 P0C0L4 CO4A_HUMAN Complement C4-A OS=Homo sapiens GN=C4A PE=1 SV=1 95 5 P04275 VWF_HUMAN von Willebrand factor OS=Homo sapiens GN=VWF PE=1 SV=4 81 6 P02675 FIBB_HUMAN Fibrinogen beta chain OS=Homo sapiens GN=FGB PE=1 SV=2 78 7 P01031 CO5_HUMAN Complement C5 OS=Homo sapiens GN=C5 PE=1 SV=4 66 8 P02768 ALBU_HUMAN Serum albumin OS=Homo sapiens GN=ALB PE=1 SV=2 66 9 P00450 CERU_HUMAN Ceruloplasmin OS=Homo sapiens GN=CP PE=1 SV=1 64 10 P02671 FIBA_HUMAN Fibrinogen alpha chain OS=Homo sapiens GN=FGA PE=1 SV=2 58 11 P08603 CFAH_HUMAN Complement factor H OS=Homo sapiens GN=CFH PE=1 SV=4 56 12 P02787 TRFE_HUMAN Serotransferrin OS=Homo sapiens GN=TF PE=1 SV=3 54 13 P00747 PLMN_HUMAN Plasminogen OS=Homo sapiens GN=PLG PE=1 SV=2 48 14 P02679 FIBG_HUMAN Fibrinogen gamma chain OS=Homo sapiens GN=FGG PE=1 SV=3 47 15 P01871 IGHM_HUMAN Ig mu chain C region OS=Homo sapiens GN=IGHM PE=1 SV=3 41 16 P04003 C4BPA_HUMAN C4b-binding protein alpha chain OS=Homo sapiens GN=C4BPA PE=1 SV=2 37 17 Q9Y6R7 FCGBP_HUMAN IgGFc-binding protein OS=Homo sapiens GN=FCGBP PE=1 SV=3 30 18 O43866 CD5L_HUMAN CD5 antigen-like OS=Homo
    [Show full text]
  • A High Throughput, Functional Screen of Human Body Mass Index GWAS Loci Using Tissue-Specific Rnai Drosophila Melanogaster Crosses Thomas J
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2018 A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses Thomas J. Baranski Washington University School of Medicine in St. Louis Aldi T. Kraja Washington University School of Medicine in St. Louis Jill L. Fink Washington University School of Medicine in St. Louis Mary Feitosa Washington University School of Medicine in St. Louis Petra A. Lenzini Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Baranski, Thomas J.; Kraja, Aldi T.; Fink, Jill L.; Feitosa, Mary; Lenzini, Petra A.; Borecki, Ingrid B.; Liu, Ching-Ti; Cupples, L. Adrienne; North, Kari E.; and Province, Michael A., ,"A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses." PLoS Genetics.14,4. e1007222. (2018). https://digitalcommons.wustl.edu/open_access_pubs/6820 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Thomas J. Baranski, Aldi T. Kraja, Jill L. Fink, Mary Feitosa, Petra A. Lenzini, Ingrid B. Borecki, Ching-Ti Liu, L. Adrienne Cupples, Kari E. North, and Michael A. Province This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/6820 RESEARCH ARTICLE A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses Thomas J.
    [Show full text]
  • Dominant Variants in the Splicing Factor PUF60 Cause a Recognizable Syndrome with Intellectual Disability, Heart Defects and Short Stature
    European Journal of Human Genetics (2017) 25, 43–51 & 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1018-4813/17 www.nature.com/ejhg ARTICLE Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature Salima El Chehadeh*,1,2, Wilhelmina S Kerstjens-Frederikse3, Julien Thevenon1,4, Paul Kuentz1,4,5, Ange-Line Bruel4, Christel Thauvin-Robinet1,4, Candace Bensignor6, Hélène Dollfus2,7, Vincent Laugel7,8, Jean-Baptiste Rivière1,4,5, Yannis Duffourd1, Caroline Bonnet9, Matthieu P Robert10,11, Rodica Isaiko12, Morgane Straub12, Catherine Creuzot-Garcher12, Patrick Calvas13, Nicolas Chassaing13, Bart Loeys14, Edwin Reyniers14, Geert Vandeweyer14, Frank Kooy14, Miroslava Hančárová15, Marketa Havlovicová15, Darina Prchalová15, Zdenek Sedláček15, Christian Gilissen16, Rolph Pfundt16, Jolien S Klein Wassink-Ruiter3 and Laurence Faivre1,4 Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C4T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing.
    [Show full text]
  • 1 Genome-Wide Meta-Analysis of Late-Onset Alzheimer's Disease Using
    medRxiv preprint doi: https://doi.org/10.1101/2021.03.14.21253553; this version posted March 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . IGAP HRC GWAS Meta-Analysis Naj et al. Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer’s Project (IGAP) Adam C. Naj1,2*#, Ganna Leonenko3*, Xueqiu Jian4*, Benjamin Grenier-Boley5*, Maria Carolina Dalmasso6*, Celine Bellenguez5*, Jin Sha1, Yi Zhao2, Sven J. van der Lee7, Rebecca Sims8, Vincent Chouraki5, Joshua C. Bis9, Brian W. Kunkle10,11, Peter Holmans8, Yuk Yee Leung2, John J. Farrell12, Alessandra Chesi2, Hung-Hsin Chen13, Badri Vardarajan14, Penelope Benchek15, Sandral Barral14, Chien-Yueh Lee2, Pavel Kuksa2, Jacob Haut1, Edward B. Lee2,16, Mingyao Li1, Yuanchao Zhang1, Struan Grant17,18, Jennifer E. Phillips-Cremins19, Hata Comic20, Achilleas Pitsillides21, Rui Xia22, Kara L. Hamilton-Nelson10, Amanda Kuzma2, Otto Valladares2, Brian Fulton-Howard23, Josee Dupuis21, Will S. Bush15, Li-San Wang2, Jennifer E. Below13, Lindsay A. Farrer12,21,24, Cornelia van Duijn20,25, Richard Mayeux14, Jonathan L. Haines15, Anita L. DeStefano21, Margaret A. Pericak-Vance10,11, Alfredo Ramirez6**, Sudha Seshadri27**, Philippe Amouyel5**, Julie Williams8**, Jean-Charles
    [Show full text]
  • Molecular Genetics of Relapsed Diffuse Large B-Cell
    cancers Review Molecular Genetics of Relapsed Diffuse Large B-Cell Lymphoma: Insight into Mechanisms of Therapy Resistance Madeleine R. Berendsen 1,2, Wendy B. C. Stevens 3, Michiel van den Brand 1,4, J. Han van Krieken 1 and Blanca Scheijen 1,2,* 1 Department of Pathology, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands; [email protected] (M.R.B.); [email protected] (M.v.d.B.); [email protected] (J.H.v.K.) 2 Radboud Institute for Molecular Life Sciences, 6525GA Nijmegen, The Netherlands 3 Department of Hematology, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands; [email protected] 4 Pathology-DNA, Rijnstate Hospital, 6815AD Arnhem, The Netherlands * Correspondence: [email protected] Received: 26 October 2020; Accepted: 26 November 2020; Published: 28 November 2020 Simple Summary: Many patients with the aggressive cancer diffuse large B-cell lymphoma (DLBCL) still respond poorly to treatment and suffer from relapsed or refractory disease. The identification of gene mutations that are responsible for the outgrowth of the relapsed tumor is crucial to understand the underlying mechanisms of therapy resistance. In this review, we provide a comprehensive overview of the affected genes and their biological functions in the context of therapy resistance. Furthermore, we discuss novel therapeutic strategies to treat patients with relapsed disease. We expect that the identification of these gene alterations in routine diagnostics holds great potential in guiding future therapy strategies in DLBCL. Abstract: The majority of patients with diffuse large B-cell lymphoma (DLBCL) can be treated successfully with a combination of chemotherapy and the monoclonal anti-CD20 antibody rituximab.
    [Show full text]
  • 1 Supplementary Materials Common Genetic Variants
    Supplementary Materials Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells Mark N. Lee, Chun Ye, Alexandra-Chloé Villani, Towfique Raj, Weibo Li, Thomas M. Eisenhaure, Selina H. Imboywa, Portia I. Chipendo, F. Ann Ran, Kamil Slowikowski, Lucas D. Ward, Khadir Raddassi, Cristin McCabe, Michelle H. Lee, Irene Y. Frohlich, David A. Hafler, Manolis Kellis, Soumya Raychaudhuri, Feng Zhang, Barbara E. Stranger, Christophe O. Benoist, Philip L. De Jager, Aviv Regev*, Nir Hacohen* *Corresponding authors. E-mail: [email protected] (A.R.); [email protected] (N.H.) This PDF file includes: Materials and Methods Supplementary Text Figs. S1 to S5 Captions for tables S1 to S11 References (46-72) Other Supplementary Materials for this manuscript includes the following: Tables S1 to S11 as zipped archive: Table S1. Samples. Table S2. Differential expression analysis. Table S3. Gene signature set. Table S4. cis-eQTLs and cis-reQTLs from pooled analysis. Table S5. Imputation meta-analysis. Table S6. Conditioning. Table S7. ChIP-Seq enrichment. Table S8. Trans-eQTLs and trans-reQTLs from pooled analysis. Table S9. Trans-eQTLs and trans-reQTLs from pooled analysis (only cis considered). Table S10. rs12805435 trans. Table S11. GWAS. 1 Materials and Methods Study subjects Donors were recruited from the Boston community as part of the Phenogenetic Project and ImmVar Consortium, and gave written informed consent for the studies. Individuals were excluded if they had a history of inflammatory disease, autoimmune disease, chronic metabolic disorders or chronic infectious disorders. For the microarray study, 30 healthy human donors were recruited. Donors were between 19 and 49 years of age; 15 were male and 15 were female; 18 were Caucasian, 6 were African-American and 6 were Asian; 12 provided a serial replicate blood sample (i.e.
    [Show full text]
  • FNBP4 Sirna (H): Sc-96663
    SANTA CRUZ BIOTECHNOLOGY, INC. FNBP4 siRNA (h): sc-96663 BACKGROUND STORAGE AND RESUSPENSION FNBP4 (formin binding protein 4), also known as FBP30 (formin-binding pro- Store lyophilized siRNA duplex at -20° C with desiccant. Stable for at least tein 30), is a 1,017 amino acid protein that contains two WW domains and one year from the date of shipment. Once resuspended, store at -20° C, binds to the Arg/Gly-rich-flanked Pro-rich domains of Formin 1, possibly reg- avoid contact with RNAses and repeated freeze thaw cycles. ulating Formin 1 function. In response to DNA damage, FNBP4 is subject to Resuspend lyophilized siRNA duplex in 330 µl of the RNAse-free water post-translational phosphorylation, probably by ATM or ATR. The gene encod- provided. Resuspension of the siRNA duplex in 330 µl of RNAse-free water ing FNBP4 maps to human chromosome 11, which houses over 1,400 genes makes a 10 µM solution in a 10 µM Tris-HCl, pH 8.0, 20 mM NaCl, 1 mM and comprises nearly 4% of the human genome. Jervell and Lange-Nielsen EDTA buffered solution. syndrome, Jacobsen syndrome, Niemann-Pick disease, hereditary angioedema and Smith-Lemli-Opitz syndrome are associated with defects in genes that APPLICATIONS maps to chromosome 11. FNBP4 siRNA (h) is recommended for the inhibition of FNBP4 expression in REFERENCES human cells. 1. Sudol, M., Chen, H.I., Bougeret, C., Einbond, A. and Bork, P. 1995. SUPPORT REAGENTS Characterization of a novel protein-binding module—the WW domain. FEBS Lett. 369: 67-71. For optimal siRNA transfection efficiency, Santa Cruz Biotechnology’s siRNA Transfection Reagent: sc-29528 (0.3 ml), siRNA Transfection Medium: 2.
    [Show full text]