DOCSLIB.ORG

Clinical Targeted Exome-Based Sequencing in Combination with Genome-Wide Copy Number Profiling: Precision Medicine Analysis of 203 Pediatric Brain Tumors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Clinical Targeted Exome-Based Sequencing in Combination with Genome-Wide Copy Number Profiling: Precision Medicine Analysis of 203 Pediatric Brain Tumors Neuro-Oncology 1 XX(XX), 1–11, 2017 | doi:10.1093/neuonc/now294 Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors Shakti H. Ramkissoon,* Pratiti Bandopadhayay,* Jaeho Hwang,* Lori A. Ramkissoon,* Noah F. Greenwald, Steven E. Schumacher, Ryan O’Rourke, Nathan Pinches, Patricia Ho, Hayley Malkin, Claire Sinai, Mariella Filbin, Ashley Plant, Wenya Linda Bi, Michael S. Chang, Edward Yang, Karen D. Wright, Peter E. Manley, Matthew Ducar, Sanda Alexandrescu, Hart Lidov, Ivana Delalle, Liliana C. Goumnerova, Alanna J. Church, Katherine A. Janeway, Marian H. Harris, Laura E. MacConaill, Rebecca D. Folkerth, Neal I. Lindeman, Charles D. Stiles, Mark W. Kieran, Azra H. Ligon, Sandro Santagata, Adrian M. Dubuc, Susan N. Chi,§ Rameen Beroukhim,§ and Keith L. Ligon§ Dana-Farber/Boston Children’s Cancer and Blood Disorders Center (P.B., M.F., A.P., M.S.C., K.D.W., P.E.M., L.C.G., K.A.J., M.W.K., S.N.C.), Department of Pathology (S.A., H.L., A.J.C., M.H.H., R.D.F., S.S., K.L.L.), Department of Radiology (E.Y.), Department of Neurosurgery (L.C.G.), Boston Children’s Hospital, Boston, Massachusetts; Department of Medical Oncology (R.B.), Oncologic Pathology (S.H.R., L.A.R., K.L.L.), Department of Pediatric Oncology (P.B., N.P., H.M., C.S., M.F., A.P., M.S.C., K.D.W., P.E.M., L.C.G., K.A.J., M.H.H., M.W.K., S.N.C.), Department of Cancer Biology (N.F.G., R.O., P.H., W.L.B., C.D.S., S.S., R.B.), Center for Cancer Genome Discovery (L.E.M., M.D.), Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Pathology (S.H.R., H.L., I.D., L.E.M., R.D.F., N.I.L., A.H.L., S.S., A.M.D., K.L.L.), Department of Neurosurgery (W.L.B., N.F.G.), Department of Medicine (R.B.), Brigham and Women’s Hospital, Boston, Massachusetts; Pratiti Bandopadhayay, Broad Institute of MIT and Harvard, Boston, Massachusetts (S.E.S., R.B., K.L.L.); Harvard Medical School, Boston, Massachusetts (S.H.R., P.B., J.H., M.F., A.P., W.L.B., E.Y., K.D.W., P.E.M., S.A., H.L., L.C.G., A.J.C., K.A.J., M.H.H., L.E.M., R.D.F., N.I.L., C.D.S., M.W.K., A.H.L., S.S., A.M.D., S.N.C., R.B., K.L.L.) §Co-corresponding and co-senior authors. Correspondence should be addressed to: Susan N. Chi, ([email protected]); Rameen Beroukhim, ([email protected]); Keith L. Ligon, ([email protected]). *These authors contributed equally to this manuscript. Abstract Background. Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established. Methods. Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to iden- tify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1–4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also per- formed to evaluate copy number alterations and better define rearrangement breakpoints. Results. Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas. Conclusion. The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diag- nostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected] 2 Ramkissoon et al. An integrative genomic analysis of 203 pediatric brain tumors Key words array CGH | brain tumor | clinical sequencing | pediatric neuro-oncology | precision medicine Importance of the study Clinically validated genomics platforms are required alterations in 55% of all patients, including identifica- for the implementation of precision medicine, tion of driver genomic mutations. In addition, we iden- including in pediatric neuro-oncology. In this study, tified alterations that confer diagnostic and prognostic we demonstrate the utility of a targeted exome- significance, such as those that allow subtyping of sequencing platform in combination with genome- medulloblastoma. Our results indicate that genomic wide copy number profiling using aCGH in a clinical profiling of pediatric brain tumors is feasible and clini- setting. These platforms detected clinically relevant cally useful. Over the last 30 years, childhood mortality from cancer Clinical Data and Review of Histology has declined significantly across most cancer types, with an average decrease of more than 50%. By contrast, how- Clinical data were extracted from clinical charts and de- ever, pediatric brain cancers have demonstrated only a identified. A histological diagnosis for each patient was 30% decrease in mortality, thus highlighting the pressing rendered for the study by at least one pediatric neuro- clinical necessity to improve diagnostics and disease man- pathologist for all cases (S.H.R.) and most cases were agement. Furthermore, from 2008 to 2012, brain tumors reviewed by a second neuropathologist. accounted for 25% of all pediatric cancer deaths.1 Although mortality has decreased, many patients suffer long-lasting and debilitating morbidities as a result of aggressive surgi- Clinical Array Comparative Genomic cal resection and high doses of radiation therapy and cyto- Hybridization toxic chemotherapy.2 High resolution array comparative genomic hybridization Across a variety of cancer types, the identification of sub- (aCGH) (Agilent Sure Print G3 Human 1 × 1M feature array) type-specific mutations has often represented a critical ini- was performed on clinical biopsy samples from formalin- tiating step in the path toward targeted therapies.3,4 Recent fixed paraffin embedded material in a CLIA-certified labora- work in pediatric brain tumors has demonstrated key dif- tory as part of clinical care using a methodology previously ferences between these tumors compared with adult coun- described.13,14 Two micrograms of patient and reference terparts. Tumors from both these cohorts show not only DNA (Promega) were fragmented and hybridized to each different incidence rates across their respective popula- microarray. The average resolution of the aCGH platform tions, but substantial variation in identified driver events.5–8 across Reference Sequence genes is 1.8 kb, and across the In order to translate these advances into clinical practice, genome 2.1 kb. physicians require a means by which to obtain accurate Analysis was performed as previously described14 and clinically relevant genomic data for these tumors. Patients clinical reports were generated by teams of board-certified require that this type of testing be affordable and widely clinical cytogeneticists, neuropathologists, and molecular accessible. Implementation of such platforms has been pathologists. well described in the adult neuro-oncology population.9–12 Herein, we report our experience of performing genomic profiling of pediatric neuro-oncology patients using a tar- Targeted Next-Generation geted exome approach in conjunction with genome-wide Sequencing—OncoPanel copy number analysis in a setting certified by the Clinical Laboratory Improvement Amendments (CLIA). For patients enrolled on the Profile clinical trial, detec- tion of mutations and gene rearrangements in tumors was achieved using targeted next-generation sequencing Methods (OncoPanel).15,16 This assay (Agilent SureSelect for target capture and Illumina HiSeq sequencing) surveys exonic Ethics Statement DNA sequences of 300 cancer genes, including 91 introns across 30 genes (Supplementary Table 1) for mutation and Ethics approval was granted by the human institutional rearrangement detection in tumor-derived DNA (minimum review board committees of the Dana-Farber/Harvard 50 ng, formalin-fixed paraffin embedded–derived tissue). Cancer Center. Informed consent was obtained from all Neuropathologists review each tumor specimen and esti- patients and/or their guardians. Targeted exome sequenc- mate the number of neoplastic cells in the submitted sam- ing was performed on tumors from patients enrolled on ple (tumor purity). OncoPanel results were interpreted and the Profile clinical study. reported by molecular pathologists, and alterations were Ramkissoon et al. An integrative genomic analysis of 203 pediatric brain tumors 3 Oncology Neuro- classified into 4 tiers (Tier 1 to Tier 4) to provide therapeu- molecular aberrations (including both single nucleotide tic and prognostic significance16 (Supplementary Table 1), variants and copy number aberrations) identified through
Load more

Recommended publications
  • Whole-Genome Landscape of Pancreatic Neuroendocrine Tumours
    Scarpa, A. et al. (2017) Whole-genome landscape of pancreatic neuroendocrine tumours. Nature, 543(7643), pp. 65-71. (doi:10.1038/nature21063) This is the author’s final accepted version. There may be differences between this version and the published version. You are advised to consult the publisher’s version if you wish to cite from it. http://eprints.gla.ac.uk/137698/ Deposited on: 12 December 2018 Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Whole-genome landscape of pancreatic neuroendocrine tumours Aldo Scarpa1,2*§, David K. Chang3,4, 7,29,36* , Katia Nones5,6*, Vincenzo Corbo1,2*, Ann-Marie Patch5,6, Peter Bailey3,6, Rita T. Lawlor1,2, Amber L. Johns7, David K. Miller6, Andrea Mafficini1, Borislav Rusev1, Maria Scardoni2, Davide Antonello8, Stefano Barbi2, Katarzyna O. Sikora1, Sara Cingarlini9, Caterina Vicentini1, Skye McKay7, Michael C. J. Quinn5,6, Timothy J. C. Bruxner6, Angelika N. Christ6, Ivon Harliwong6, Senel Idrisoglu6, Suzanne McLean6, Craig Nourse3, 6, Ehsan Nourbakhsh6, Peter J. Wilson6, Matthew J. Anderson6, J. Lynn Fink6, Felicity Newell5,6, Nick Waddell6, Oliver Holmes5,6, Stephen H. Kazakoff5,6, Conrad Leonard5,6, Scott Wood5,6, Qinying Xu5,6, Shivashankar Hiriyur Nagaraj6, Eliana Amato1,2, Irene Dalai1,2, Samantha Bersani2, Ivana Cataldo1,2, Angelo P. Dei Tos10, Paola Capelli2, Maria Vittoria Davì11, Luca Landoni8, Anna Malpaga8, Marco Miotto8, Vicki L.J. Whitehall5,12,13, Barbara A. Leggett5,12,14, Janelle L. Harris5, Jonathan Harris15, Marc D. Jones3, Jeremy Humphris7, Lorraine A. Chantrill7, Venessa Chin7, Adnan M. Nagrial7, Marina Pajic7, Christopher J. Scarlett7,16, Andreia Pinho7, Ilse Rooman7†, Christopher Toon7, Jianmin Wu7,17, Mark Pinese7, Mark Cowley7, Andrew Barbour18, Amanda Mawson7†, Emily S.
    [Show full text]
  • Pediatric and Perinatal Pathology (1842-1868)
    VOLUME 33 | SUPPLEMENT 2 | MARCH 2020 MODERN PATHOLOGY ABSTRACTS PEDIATRIC AND PERINATAL PATHOLOGY (1842-1868) LOS ANGELES CONVENTION CENTER FEBRUARY 29-MARCH 5, 2020 LOS ANGELES, CALIFORNIA 2020 ABSTRACTS | PLATFORM & POSTER PRESENTATIONS EDUCATION COMMITTEE Jason L. Hornick, Chair William C. Faquin Rhonda K. Yantiss, Chair, Abstract Review Board Yuri Fedoriw and Assignment Committee Karen Fritchie Laura W. Lamps, Chair, CME Subcommittee Lakshmi Priya Kunju Anna Marie Mulligan Steven D. Billings, Interactive Microscopy Subcommittee Rish K. Pai Raja R. Seethala, Short Course Coordinator David Papke, Pathologist-in-Training Ilan Weinreb, Subcommittee for Unique Live Course Offerings Vinita Parkash David B. Kaminsky (Ex-Officio) Carlos Parra-Herran Anil V. Parwani Zubair Baloch Rajiv M. Patel Daniel Brat Deepa T. Patil Ashley M. Cimino-Mathews Lynette M. Sholl James R. Cook Nicholas A. Zoumberos, Pathologist-in-Training Sarah Dry ABSTRACT REVIEW BOARD Benjamin Adam Billie Fyfe-Kirschner Michael Lee Natasha Rekhtman Narasimhan Agaram Giovanna Giannico Cheng-Han Lee Jordan Reynolds Rouba Ali-Fehmi Anthony Gill Madelyn Lew Michael Rivera Ghassan Allo Paula Ginter Zaibo Li Andres Roma Isabel Alvarado-Cabrero Tamara Giorgadze Faqian Li Avi Rosenberg Catalina Amador Purva Gopal Ying Li Esther Rossi Roberto Barrios Anuradha Gopalan Haiyan Liu Peter Sadow Rohit Bhargava Abha Goyal Xiuli Liu Steven Salvatore Jennifer Boland Rondell Graham Yen-Chun Liu Souzan Sanati Alain Borczuk Alejandro Gru Lesley Lomo Anjali Saqi Elena Brachtel Nilesh Gupta Tamara
    [Show full text]
  • PDF Datasheet
    Product Datasheet BEND2 Overexpression Lysate NBL1-09637 Unit Size: 0.1 mg Store at -80C. Avoid freeze-thaw cycles. Protocols, Publications, Related Products, Reviews, Research Tools and Images at: www.novusbio.com/NBL1-09637 Updated 3/17/2020 v.20.1 Earn rewards for product reviews and publications. Submit a publication at www.novusbio.com/publications Submit a review at www.novusbio.com/reviews/destination/NBL1-09637 Page 1 of 2 v.20.1 Updated 3/17/2020 NBL1-09637 BEND2 Overexpression Lysate Product Information Unit Size 0.1 mg Concentration The exact concentration of the protein of interest cannot be determined for overexpression lysates. Please contact technical support for more information. Storage Store at -80C. Avoid freeze-thaw cycles. Buffer RIPA buffer Target Molecular Weight 87.7 kDa Product Description Description Transient overexpression lysate of BEN domain containing 2 (BEND2) The lysate was created in HEK293T cells, using Plasmid ID RC206228 and based on accession number NM_153346. The protein contains a C-MYC/DDK Tag. Gene ID 139105 Gene Symbol BEND2 Species Human Notes HEK293T cells in 10-cm dishes were transiently transfected with a non-lipid polymer transfection reagent specially designed and manufactured for large volume DNA transfection. Transfected cells were cultured for 48hrs before collection. The cells were lysed in modified RIPA buffer (25mM Tris-HCl pH7.6, 150mM NaCl, 1% NP-40, 1mM EDTA, 1xProteinase inhibitor cocktail mix, 1mM PMSF and 1mM Na3VO4, and then centrifuged to clarify the lysate. Protein concentration was measured by BCA protein assay kit.This product is manufactured by and sold under license from OriGene Technologies and its use is limited solely for research purposes.
    [Show full text]
  • Misexpression of Cancer/Testis (Ct) Genes in Tumor Cells and the Potential Role of Dream Complex and the Retinoblastoma Protein Rb in Soma-To-Germline Transformation
    Michigan Technological University Digital Commons @ Michigan Tech Dissertations, Master's Theses and Master's Reports 2019 MISEXPRESSION OF CANCER/TESTIS (CT) GENES IN TUMOR CELLS AND THE POTENTIAL ROLE OF DREAM COMPLEX AND THE RETINOBLASTOMA PROTEIN RB IN SOMA-TO-GERMLINE TRANSFORMATION SABHA M. ALHEWAT Michigan Technological University, [email protected] Copyright 2019 SABHA M. ALHEWAT Recommended Citation ALHEWAT, SABHA M., "MISEXPRESSION OF CANCER/TESTIS (CT) GENES IN TUMOR CELLS AND THE POTENTIAL ROLE OF DREAM COMPLEX AND THE RETINOBLASTOMA PROTEIN RB IN SOMA-TO- GERMLINE TRANSFORMATION", Open Access Master's Thesis, Michigan Technological University, 2019. https://doi.org/10.37099/mtu.dc.etdr/933 Follow this and additional works at: https://digitalcommons.mtu.edu/etdr Part of the Cancer Biology Commons, and the Cell Biology Commons MISEXPRESSION OF CANCER/TESTIS (CT) GENES IN TUMOR CELLS AND THE POTENTIAL ROLE OF DREAM COMPLEX AND THE RETINOBLASTOMA PROTEIN RB IN SOMA-TO-GERMLINE TRANSFORMATION By Sabha Salem Alhewati A THESIS Submitted in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE In Biological Sciences MICHIGAN TECHNOLOGICAL UNIVERSITY 2019 © 2019 Sabha Alhewati This thesis has been approved in partial fulfillment of the requirements for the Degree of MASTER OF SCIENCE in Biological Sciences. Department of Biological Sciences Thesis Advisor: Paul Goetsch. Committee Member: Ebenezer Tumban. Committee Member: Zhiying Shan. Department Chair: Chandrashekhar Joshi. Table of Contents List of figures .......................................................................................................................v
    [Show full text]
  • Pancreatic Cancer Metabolism
    Published OnlineFirst March 3, 2017; DOI: 10.1158/2159-8290.CD-RW2017-044 RESEARCH WATCH Pancreatic Cancer Major finding: PanNET mutations affect Concept: Comprehensive molecular anal- Impact: The comprehensive identifica- DNA damage repair, chromatin remodeling, ysis of 102 clinically sporadic PanNETs tion of PanNET genetic alterations may telomere maintenance, and mTOR signaling. uncovers essential PanNET pathways. aid risk stratification and treatment. WHOLE-GENOME SEQUENCING DEFINES THE MUTATIONAL LANDSCAPE OF PanNETS Pancreatic neuroendocrine tumors (PanNET) are exhibited increased telomere length. There were classifi ed into three groups: low grade (G1), inter- an average of 29 structural rearrangements per mediate grade (G2), and high grade (G3). G3 Pan- tumor, with rearrangements leading to inactiva- NETs have a universally poor prognosis, whereas tion of tumor suppressors such as MTAP, ARID2, G1 and G2 tumors have an unpredictable clinical SMARCA4, MLL3, CDKN2A, and SETD2, or creating course. A better understanding of the molecular oncogenic gene fusions. In total, 66 somatic in- underpinnings of the disease may enable better frame gene fusions were identifi ed, including three risk stratifi cation and the identifi cation of patients EWSR1 fusion events leading to EWSR1–BEND2 or who might benefi t from early aggressive therapy. Scarpa and EWSR1–FLI1. Although EWSR1–FLI1 is a characteristic Ewing colleagues performed comprehensive molecular analyses of sarcoma fusion gene, the morphologic and pathologic features 102 clinically sporadic PanNETs. Whole-genome sequencing were consistent with PanNETs. RNA sequencing of 30 Pan- of 98 PanNETs defi ned fi ve distinct mutational signatures: NET tumors found that common genetic alterations affected MUTYH, APOBEC, BRCA-defi ciency, age, and COSMIC signa- DNA damage and repair, chromatin remodeling, telomere ture 5.
    [Show full text]
  • Marine Mammal Protection Act and Endangered Species Act Lmplementation Program 1 999
    National Marine Fisheries Service U.S DEPARTMENT OF COMMERCE AFSC PROCESSED REPORT 2OOO.1 1 Marine Mammal Protection Act and Endangered Species Act lmplementation Program 1 999 December 2000 This report does not constitute a publication and is for information only. All data herein are to be considered provisional. ERRATA NOTICE This document is being made available in .PDF format for the convenience of users; however, the accuracy and correctness of the document can only be certified as was presented in the original hard copy format. Inaccuracies in the OCR scanning process may influence text searches of the .PDF file. Light or faded ink in the original document may also affect the quality of the scanned document. Marine Mammal Protection Act and Endangered Species Act Implementation Program 1999 Edited by: Anita L. Lopez Douglas P. DeMaster Annual Reports ofresearch carried out on the population biologt of marine mammals by the National Marine Mammal Laboratory to meet the 1994 amendments to the Marine Mammal Protection Act and the Endangered Species Act Submitted to: Office of Protected Resources National Marine Fisheries Service 1335 East-West Highway Silver Spring, MD 20910 National Oceanic and Atmospheric Administration National Marine Fisheries Service Alaska Fisheries Science Center National Marine Mammal Laboratory 7600 Sand Point Way Northeast Seattle, WA 98115-0070 December 2000 Preface Beginning in 1991, the National Marine Mammal Laboratory NMML) has been partially funded by the National Marine Fisheries Service's (NÀ/ßS) Office of Protected Resources to determine the abundance of selected species in U.S. waters of the eastern North Pacific Ocean.
    [Show full text]
  • Single-Cell RNA Sequencing of Human, Macaque, and Mouse Testes Uncovers Conserved and Divergent Features of Mammalian Spermatogenesis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.03.17.994509; this version posted March 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Single-cell RNA sequencing of human, macaque, and mouse testes uncovers conserved and divergent features of mammalian spermatogenesis Adrienne Niederriter Shami1,7, Xianing Zheng1,7, Sarah K. Munyoki2,7, Qianyi Ma1, Gabriel L. Manske3, Christopher D. Green1, Meena Sukhwani2, , Kyle E. Orwig2*, Jun Z. Li1,4*, Saher Sue Hammoud1,3,5,6,8* 1Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA 2 Department of Obstetrics, Gynecology and Reproductive Sciences, Integrative Systems Biology Graduate Program, Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA. 3 Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA 4 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA 5 Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA 6Department of Urology, University of Michigan, Ann Arbor, MI, USA 7 These authors contributed equally 8 Lead Contact * Correspondence: [email protected] (K.E.O.), [email protected] (J.Z.L.), [email protected] (S.S.H.) bioRxiv preprint doi: https://doi.org/10.1101/2020.03.17.994509; this version posted March 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Summary Spermatogenesis is a highly regulated process that produces sperm to transmit genetic information to the next generation.
    [Show full text]
  • View a Copy of This Licence, Visit
    Robertson et al. BMC Biology (2020) 18:103 https://doi.org/10.1186/s12915-020-00826-z RESEARCH ARTICLE Open Access Large-scale discovery of male reproductive tract-specific genes through analysis of RNA-seq datasets Matthew J. Robertson1,2, Katarzyna Kent3,4,5, Nathan Tharp3,4,5, Kaori Nozawa3,5, Laura Dean3,4,5, Michelle Mathew3,4,5, Sandra L. Grimm2,6, Zhifeng Yu3,5, Christine Légaré7,8, Yoshitaka Fujihara3,5,9,10, Masahito Ikawa9, Robert Sullivan7,8, Cristian Coarfa1,2,6*, Martin M. Matzuk1,3,5,6 and Thomas X. Garcia3,4,5* Abstract Background: The development of a safe, effective, reversible, non-hormonal contraceptive method for men has been an ongoing effort for the past few decades. However, despite significant progress on elucidating the function of key proteins involved in reproduction, understanding male reproductive physiology is limited by incomplete information on the genes expressed in reproductive tissues, and no contraceptive targets have so far reached clinical trials. To advance product development, further identification of novel reproductive tract-specific genes leading to potentially druggable protein targets is imperative. Results: In this study, we expand on previous single tissue, single species studies by integrating analysis of publicly available human and mouse RNA-seq datasets whose initial published purpose was not focused on identifying male reproductive tract-specific targets. We also incorporate analysis of additional newly acquired human and mouse testis and epididymis samples to increase the number of targets identified. We detected a combined total of 1178 genes for which no previous evidence of male reproductive tract-specific expression was annotated, many of which are potentially druggable targets.
    [Show full text]
  • Molecular Clarification of Brainstem Astroblastoma with EWSR1‐ BEND2 Fusion in a 38‐Year‐Old Man
    Free Neuropathology 2:16 (2021) Smith‐Cohn et al doi: https://doi.org/10.17879/freeneuropathology‐2021‐3334 page 1 of 8 Case Report Molecular clarification of brainstem astroblastoma with EWSR1‐ BEND2 fusion in a 38‐year‐old man Matthew A. Smith‐Cohn,1,2 Zied Abdullaev,3 Kenneth D. Aldape,3 Martha Quezado,3 Marc K. Rosenblum,4 Chad M. Vanderbilt,4 Fausto J. Rodriguez,5 John Laterra,**2 Charles G. Eberhart**5 1 Neuro‐Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 2 Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 3 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA 4 Department of Pathology, Memorial Sloan‐Kettering Cancer Center, New York, NY, USA 5 Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA ** These authors contributed equally to this manuscript Corresponding author: Charles Eberhart, MD, Ph.D. ∙ Department of Pathology ∙ The Johns Hopkins University School of Medicine ∙ 1800 Orleans St. ∙ Sheikh Zayed Tower ∙ Baltimore, MD 21287 ∙ USA [email protected] Submitted: 21 April 2021 ∙ Accepted: 17 June 2021 ∙ Copyedited by: Calixto‐Hope Lucas ∙ Published: 21. June 2021 Abstract The majority of astroblastoma occur in a cerebral location in children and young adults. Here we describe the unusual case of a 38‐year‐old man found to have a rapidly growing cystic enhancing circumscribed brainstem tumor with high grade histopathology classified as astroblastoma, MN1‐altered by methylome profiling. He was treated with chemoradiation and temozolomide followed by adjuvant temozolomide without progression to date over one year from treatment initiation.
    [Show full text]
  • Cxorf20 (BEND2) (NM 153346) Human Untagged Clone Product Data
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for SC125926 CXorf20 (BEND2) (NM_153346) Human Untagged Clone Product data: Product Type: Expression Plasmids Product Name: CXorf20 (BEND2) (NM_153346) Human Untagged Clone Tag: Tag Free Symbol: BEND2 Synonyms: CXorf20 Vector: pCMV6-XL5 E. coli Selection: Ampicillin (100 ug/mL) Cell Selection: None Fully Sequenced ORF: >OriGene sequence for NM_153346 edited GGTGTCTCGGACAACGAGTGTACGCAGTTACCACACAGTTACCAAGCAGTTACCTCAGAG CCGCGGCGCAGACGTAGGCCTCAGGTCTCGGGCCTCAGGTCTCGGGCCTCAGAGCCAGAC CCCGCCATCTCACGATGTCAGAGAGGACCCAGGAACAGGATTTTGTTATTATAACTGTCG ACGACAGTGATGATAACAATGATTGCAGTATTGAGATGGTGGAAGTTTCTGAAACAGCAG ATAATTCCACTAATGACATAGCAGATGATTCCACTTATGTCACAGCAGATAATCCCACTG ATGACACAGCCACACAACCAAATTTTCCAGGCGGCAATGATGGCCATCACCGTCCACTCC AAATGTCATATGGGTCTGGCTCTGTCACCCAGGCTGGAGTGCAGTGGCATGATCACAGCT CACTGCAGCCTCAACCTCTTGGACTCAAGCAATTCTTCCACCTCAGCCTTCCCAGTAGCT GGGATGACAGGCGCACGCCACCATGCCCAGTAGCCCATGGTGACCAAATAGTTTCACAGA TAAACCACCCAGTACATTTAAGAAGATACAGTTACAACTCAGAGGAAGTGGATTTTCCAA AAAGAGGAAGATTCTATACTCCAGAGGTACAGTCTAGCATATCACCACCAGCGGAAAGGC AGGAAACCCATGCCTGGGCCAGCCCTGCTGTAACATCTCTTGAGTCAGCAGCATGTCATG AACTGCAGGAAGCAGACCTCAGTGAGAGTTTATCATATCCCAGAATTGTCTCCTCAAGTT CATTACAGCAGTATGTCGCACAAGGTGGCTCATTTCCTTGTTTCGGTATGCCATGGAACT TTATCAGTGGAGGTGCTGAAAGTACCAATGCTGTCATCTCATTTGCCAATGCTACTACAG CAGTACCTATGGCAGTTCTGTCACGAAGAGAATCCAGTCTGGCAAATAACCCTGGTGTGG TGAATTACTCTGCTCTACCAGAAAATGAAAATGTGGGCCCAGGTAGAGCCTTGTCATCTT
    [Show full text]
  • Thesis Master Doc Revamp
    The impact of Alu elements on the human proteome Sarah Elizabeth Atkinson Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Chemistry May 2019 Acknowledgements Acknowledgements Firstly, I would like to thank Prof. Paul Taylor, Dr Michael Webb and Dr Suzanne Dilly for their guidance and support throughout my PhD, as well as the University of Leeds and Valirx Plc for providing me with this wonderful opportunity. Secondly, I would like to extend my deepest thanks to the members of Lab 1.49, past and present, for all the support they have provided throughout my PhD. In particular, I would like to thank Jack Caudwell for providing me with constant moral support and always keeping a smile on my face, as well as helping to provide the warm and social atmosphere that makes working in 1.49 so special. You made my entire PhD experience infinitely more enjoyable! To Ryan, I hope your next desk buddy is more of a pushover and your future desk take overs are more successful than they were with me. Additionally, I would like to thank Pablo, Devón and JoDo for providing me with friendship and support both inside and outside of the university. It is, of course, customary to thank my parents, who have allowed me to remain in debt with the ‘Bank of Mum and Dad’ whilst I have postponed getting a ‘real job’ for as long as physically possible. On a more serious note, they have always provided me with the upmost support and it has never gone unappreciated.
    [Show full text]
  • Nearly All New Protein-Coding Predictions in the CHESS Database Are Not Protein-Coding Irwin Jungreis*,✝,1,2, Michael L
    bioRxiv preprint doi: https://doi.org/10.1101/360602; this version posted July 2, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Nearly all new protein-coding predictions in the CHESS database are not protein-coding Irwin Jungreis*,✝,1,2, Michael L. Tress*,3, Jonathan Mudge*,4, Cristina Sisu5,6, Toby Hunt4, Rory Johnson7,8, Barbara Uszczynska-Ratajczak9, Julien Lagarde10,11,12, James Wright13, Paul Muir14,15, Mark Gerstein5,16,17, Roderic Guigo10,11,12, Manolis Kellis1,2, Adam Frankish✝,4, Paul Flicek4, The GENCODE Consortium 1MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA; 2Broad Institute of MIT and Harvard, Cambridge, MA; 3Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain; 4European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK; 5Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; 6Department of Bioscience, Brunel University London, Uxbridge, UB8 3PH, UK; 7Department of Medical Oncology, Inselspital, University Hospital, University of Bern, Bern, Switzerland; 8Department of Biomedical Research (DBMR), University of Bern, Bern, Switzerland; 9Centre of New Technologies, University of Warsaw, Warsaw, Poland; 10Centre for Genomic Regulation (CRG), The Barcelona Institute for
    [Show full text]