DOCSLIB.ORG

The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma Vandana Sandhu1,2, David C

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma Vandana Sandhu1,2, David C Published OnlineFirst August 3, 2016; DOI: 10.1158/0008-5472.CAN-16-0658 Cancer Molecular and Cellular Pathobiology Research The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma Vandana Sandhu1,2, David C. Wedge3,4, Inger Marie Bowitz Lothe1,5, Knut Jørgen Labori6, Stefan C. Dentro3,4,Trond Buanes6,7, Martina L. Skrede1, Astrid M. Dalsgaard1, Else Munthe8, Ola Myklebost8, Ole Christian Lingjærde9, Anne-Lise Børresen-Dale1,7, Tone Ikdahl10,11, Peter Van Loo12,13, Silje Nord1, and Elin H. Kure1,2 Abstract Despite advances in diagnostics, less than 5% of patients with and Wnt signaling. By integrating genomics and transcrip- periampullary tumors experience an overall survival of five years tomics data from the same patients, we identified CCNE1 and or more. Periampullary tumors are neoplasms that arise in the ERBB2 as candidate driver genes. Morphologic subtypes of vicinity of the ampulla of Vater, an enlargement of liver and periampullary adenocarcinomas (i.e., pancreatobiliary or intes- pancreas ducts where they join and enter the small intestine. In tinal) harbor many common genomic aberrations. However, this study, we analyzed copy number aberrations using Affymetrix gain of 13q and 3q, and deletions of 5q were found specificto SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo the intestinal subtype. Our study also implicated the use of the University Hospital to identify genome-wide copy number aber- PAM50 classifier in identifying a subgroup of patients with a rations, putative driver genes, deregulated pathways, and poten- high proliferation rate, which had impaired survival. Further- tial prognostic markers. Results were validated in a separate cohort more, gain of 18p11 (18p11.21-23, 18p11.31-32) and 19q13 derived from The Cancer Genome Atlas Consortium (n ¼ 127). (19q13.2, 19q13.31-32) and subsequent overexpression of the In contrast to many other solid tumors, periampullary adeno- genes in these loci were associated with impaired survival. carcinomas exhibited more frequent genomic deletions than Our work identifies potential prognostic markers for periampul- gains. Genes in the frequently codeleted region 17p13 and lary tumors, the genetic characterization of which has lagged. 18q21/22 were associated with cell cycle, apoptosis, and p53 Cancer Res; 76(17); 1–11. Ó2016 AACR. Introduction evolution is driven either by mutations or by copy number aberrations (CNA; ref. 2). CNAs play a critical role in activating Pancreatic cancer is the fourth most common cause of cancer- oncogenes and inactivating tumor suppressor genes, thereby related deaths in Western countries, and it is projected to be the targeting the hallmarks of cancer (3, 4). Studies have shown that second leading cause of cancer-related death by 2030 (1). The driver alterations in pancreatic cancer include both single-nucle- incidence and mortality rate for pancreatic cancer are almost equal otide variants and large-scale rearrangements (5, 6). In the field of and the 5-year survival rate is <5%. Across tumor types, tumor cancer genomics, the focus has been on identifying altered geno- mic regions and pathways by high-throughput technologies, and relating these to phenotypic effects. This knowledge has already 1Department of Cancer Genetics, Institute for Cancer Research, Oslo led to substantial advances in diagnostics and therapeutics in University Hospital, Oslo, Norway. 2Department for Environmental other cancers such as targeting the HER2 oncogene in breast cancer Health and Science, University College of Southeast Norway, Bø, Norway. 3Wellcome Trust Sanger Institute, Hinxton, United Kingdom. patients using the mAb trastuzumab (7). 4Department of Cancer Genomics, Big Data Institute, University of A number of studies are published on pancreatic ductal Oxford, Oxford, United Kingdom. 5Department of Pathology, Oslo adenocarcinomas (PDAC) using high-throughput data analysis 6 University Hospital, Oslo, Norway. Department of Hepato-Pan- (8–14). Previous studies on relatively small cohorts of PDAC creato-Biliary Surgery, Oslo University Hospital, Oslo, Norway. 7Insti- tute of Clinical Medicine, University of Oslo, Oslo, Norway. 8Depart- have documented homozygous deletions of 1p, 3p, 6p, 9p, ment of Tumor Biology, Institute for Cancer Research, Oslo University 12q, 13q, 14q, 17p, and 18q, and amplifications of 1q, 2q, 3q, 9 Hospital, Oslo, Norway. Department of Computer Science, University 5q, 7p, 7q, 8q, 11p, 14q, 17q, and 20q (11–13). Recently, a of Oslo, Oslo, Norway. 10Department of Oncology, Oslo University Hospital, Oslo, Norway. 11Akershus University Hospital, Nordbyhagen, study of 75 PDAC and 25 cell lines derived from PDAC patients Norway. 12The Francis Crick Institute, London, United Kingdom. were analyzed using Illumina SNP arrays and whole genome 13 Department of Human Genetics, University of Leuven, Leuven, SOLID sequencing (5). The results showed that genomic altera- Belgium. tions in PDACs are dominated by structural alterations, and Note: Supplementary data for this article are available at Cancer Research were classified by the number and distribution of structural Online (http://cancerres.aacrjournals.org/). variation events. Another recent publication identified four Corresponding Author: Elin H. Kure, Institute for Cancer Research, Ullernchau- subtypes of PDAC namely squamous, pancreatic progenitor, seen 70, Oslo 0310, Norway. Phone: 472-278-1377; Fax: 472-278-1395; E-mail: immunogenic, and aberrantly differentiated endocrine exocrine [email protected] type (14), which overlapped with Collisson subtypes namely doi: 10.1158/0008-5472.CAN-16-0658 quasi-mesenchymal, exocrine, and classical subtype, except for Ó2016 American Association for Cancer Research. the immunogenic subtype (8, 14). Despite these studies, our www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst August 3, 2016; DOI: 10.1158/0008-5472.CAN-16-0658 Sandhu et al. knowledge about pancreatic cancer subtypes is limited, partly results, 127 PDAC samples from the TCGA cohort https://tcga- due to small samples sizes and lack of validation in different data.nci.nih.gov/tcga/ were analyzed. cohorts. Here we analyzed the copy number profile of 60 tumors from Affymetrix SNP 6.0 arrays Oslo University Hospital (OUH; Oslo, Norway) and 127 tumors The Affymetrix SNP 6.0 arrays include 1.8 million genetic from The Cancer Genome Atlas (TCGA) cohort using SNP arrays. markers, including 906,600 SNPs and 946,000 copy number Because of the low tumor purity frequently observed in pancreatic probes. DNA digestion, labeling, and hybridization were per- cancer biopsies, copy number alterations may present as subtle formed according to the manufacturer's instruction (Affymetrix). changes in copy number signals. The Battenberg analysis pipeline applied herein (ref. 15; doi: 10.5281/zenodo.16107) performs Statistical analysis phasing of both parental haplotypes to increase sensitivity. CNAs Copy number aberration profiles from the OUH (n ¼ 60) and were identified in tumors originating from the pancreatic ducts, the TCGA (n ¼ 127) cohort were generated. Segmental copy the bile duct, the ampulla and the duodenum, collectively called number information was derived for each sample using the periampullary adenocarcinomas in the OUH cohort of 60 Battenberg pipeline (https://github.com/cancerit/cgpBattenberg/) patients. Several regions of recurrent gain or loss were identified as described previously (15) to estimate tumor cell fraction, tumor in the OUH cohort and validated in TCGA cohort, providing a set ploidy, and copy numbers. The Battenberg pipeline has high of putative driver genes and deregulated pathways in periampul- sensitivity for samples with low cellularity, frequently observed lary adenocarcinomas. The frequent gain and overexpression of in pancreatic tumors. Briefly, the tool phases heterozygous SNPs genes was further associated with poor patient prognosis. with use of the 1000 genomes genotypes as a reference panel using Impute2 (17), and corrects phasing errors in regions with copy Materials and Methods number changes through segmentation (18). After segmentation of the resulting B-allele frequency (BAF) values, t tests are per- DNA extraction formed on the BAFs of each copy number segment to identify DNA was extracted from tumor tissue using the Maxwell Tissue whether they correspond to the value resulting from a fully clonal fl fi DNA kit on the Maxwell 16 Instrument (Promega). Brie y, ve 20- copy number change. If not, the copy number segment is repre- m m m sections were homogenized in 300- L lysis buffer and added sented as a mixture of two different copy number states, with fi to the cartridge. The method is based on puri cation using the fraction of cells bearing each copy number state estimated paramagnetic particles as a mobile solid phase for capturing, from the average BAF of the heterozygous SNPs in that segment. washing, and elution of genomic DNA. Elution volume was The genome instability indices (GII) were calculated for both m 200 L. DNA was extracted from 6-mL EDTA blood using the the cohorts; it is measured as the fraction of aberrant probes QiAamp DNA Blood BioRobot MDx Kit on the BioRobot MDx throughout the genome above or below the ploidy. Correlation (Qiagen). This was done at Aros Applied Biotechnology AS, and analysis was carried out to identify any association between GII the Department of Medical Genetics, Oslo University Hospital and
Load more

Recommended publications
  • Bayesian Hierarchical Modeling of High-Throughput Genomic Data with Applications to Cancer Bioinformatics and Stem Cell Differentiation
    BAYESIAN HIERARCHICAL MODELING OF HIGH-THROUGHPUT GENOMIC DATA WITH APPLICATIONS TO CANCER BIOINFORMATICS AND STEM CELL DIFFERENTIATION by Keegan D. Korthauer A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Statistics) at the UNIVERSITY OF WISCONSIN–MADISON 2015 Date of final oral examination: 05/04/15 The dissertation is approved by the following members of the Final Oral Committee: Christina Kendziorski, Professor, Biostatistics and Medical Informatics Michael A. Newton, Professor, Statistics Sunduz Kele¸s,Professor, Biostatistics and Medical Informatics Sijian Wang, Associate Professor, Biostatistics and Medical Informatics Michael N. Gould, Professor, Oncology © Copyright by Keegan D. Korthauer 2015 All Rights Reserved i in memory of my grandparents Ma and Pa FL Grandma and John ii ACKNOWLEDGMENTS First and foremost, I am deeply grateful to my thesis advisor Christina Kendziorski for her invaluable advice, enthusiastic support, and unending patience throughout my time at UW-Madison. She has provided sound wisdom on everything from methodological principles to the intricacies of academic research. I especially appreciate that she has always encouraged me to eke out my own path and I attribute a great deal of credit to her for the successes I have achieved thus far. I also owe special thanks to my committee member Professor Michael Newton, who guided me through one of my first collaborative research experiences and has continued to provide key advice on my thesis research. I am also indebted to the other members of my thesis committee, Professor Sunduz Kele¸s,Professor Sijian Wang, and Professor Michael Gould, whose valuable comments, questions, and suggestions have greatly improved this dissertation.
    [Show full text]
  • The Genetic Material: DNA the Central Dogma of Genetics
    The Genetic material: DNA The Central Dogma of Genetics DNA transcription Reverse tititranscriptio RNA n translation Protein • A, T, G, C in DNA • A, U, G, C in RNA • DNA is double stranded • DNA has po lar ity 5’ to 3’ • A T base pair, G C base pair • RNA is single stranded, also has polarity , generally referred as upstream and downstream. In RNA: A U base pair G C base pair. This type of base pa iri ng i n RNA causes secon dary st ruct ure. 1. 5’ vs 3’ 2. Purines vs. Pyrimidines 3. A vs. G 4. C vs. T 5. Transitions vs. transversions AT/GC ratios and their applications • Genome composition and chtitiharacterization • Implications in sequencing • Primer design • PCR yields • … The Polarity of DNA Higher order organization of genomes Most chromosomal DNA does not code for proteins or RNAs: e.g., Human genome 3 billion base pairs 25,000 genes x 2,000 bp per gene =5x10= 5 x 107 bp 5 x 107/3 x 109 = 1.67% MlMolecu lar P rob es: The tools of molecular genetics Concept of probes • “For diagnostic tests, the agent that is used to detect the presence of a molecule in the sample”. • “A DNA sequence that is used to detect the presence o f a comp lement ary sequence by hybridization with a nucleic acid sample”. Need for probes • Screen for the gene of interest • Southern blot to understand genomic structure and gene copy numbers • Northern blot for analysis of RNA expression • Verification of allelic amplification in PCR • ..
    [Show full text]
  • 1 Mechanistic Studies of DNA Replication, Lesion Bypass, And
    Mechanistic Studies of DNA Replication, Lesion Bypass, and Editing Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Austin Tyler Raper, B.S. The Ohio State University Biochemistry Graduate Program The Ohio State University 2018 Dissertation Committee Dr. Zucai Suo, Advisor Dr. Ross Dalbey Dr. Michael Poirier Dr. Richard Swenson 1 Copyrighted by Austin Tyler Raper 2018 2 Abstract DNA acts as a molecular blueprint for life. Adenosine, cytidine, guanosine, and thymidine nucleotides serve as the building blocks of DNA and can be arranged in near- endless combinations. These unique sequences of DNA may encode genes that when expressed produce RNA, proteins, and enzymes responsible for executing diverse tasks necessary for biological existence. Accordingly, careful maintenance of the molecular integrity of DNA is paramount for the growth, development, and functioning of organisms. However, DNA is damaged upon reaction with pervasive chemicals generated by normal cellular metabolism or encountered through the environment. The resulting DNA lesions act as roadblocks to high-fidelity A- and B-family DNA polymerases responsible for replicating DNA in preparation for cell division which may lead to programmed cell death. Additionally, these lesions may fool the polymerase into making errors during DNA replication, leading to genetic mutations and cancer. Fortunately, the cell has evolved DNA damage tolerance as an emergency response to such lesions. During DNA damage tolerance, a damage-stalled high-fidelity polymerase is substituted for a specialized Y-family polymerase, capable of bypassing the offending DNA lesion, for replication to continue.
    [Show full text]
  • Anti-Cdk8 Antibody Produced in Rabbit (C0238)
    ANTI-CDK8 Developed in Rabbit, Affinity Isolated Antibody Product Number C 0238 Product Description Reagent Anti-Cyclin-Dependent Kinase 8 (CDK8) is developed in Anti-CDK8, at approximately 1 mg/ml, is supplied as a rabbit using a synthetic peptide corresponding to the solution in phosphate buffered saline, pH 7.4 containing C-terminal region (aa 451-464) of human CDK8. The 0.2% BSA and 15 mM sodium azide. antibody is purified by protein A affinity chromatography. Anti-CDK8 specifically recognizes a 54 kDa protein Precautions and Disclaimer identified as cyclin-dependent kinase 8 (CDK8). Anti- Due to the sodium azide content, a material safety data CDK8 does not crossreact with the other members of sheet (MSDS) for this product has been sent to the CDK family. It detects human, mouse and rat CDK8. It attention of the safety officer of your institution. Consult is used in immunoblotting, immunoprecipitation and the MSDS for information regarding hazardous and safe immunofluorescence applications. handling practices. Cyclin-dependent kinase 8 (CDK8) is a 464-amino acid Storage/Stability protein containing the sequence motifs and 11 Store at –20 °C. For extended storage, upon initial subdomains characteristic of a serine/threonine-specific thawing, freeze the solution in working aliquots. kinase.1 CDKs become activated through binding to Avoid repeated freezing and thawing to prevent cyclins, formation of cyclin-CDK complexes and denaturing the antibody. Storage in “frost-free” reversible phosphorylation reactions. Cyclin-CDK freezers is also not recommended. If slight complexes directly control progression through G1, S, turbidity occurs upon prolonged storage, clarify the G2 and M phases of the cell division cycle.
    [Show full text]
  • Snotarget Shows That Human Orphan Snorna Targets Locate Close to Alternative Splice Junctions
    Available online at www.sciencedirect.com Gene 408 (2008) 172–179 www.elsevier.com/locate/gene snoTARGET shows that human orphan snoRNA targets locate close to alternative splice junctions Peter S. Bazeley a, Valery Shepelev b, Zohreh Talebizadeh c, Merlin G. Butler c, Larisa Fedorova d, ⁎ Vadim Filatov e, Alexei Fedorov a,d, a Program in Bioinformatics and Proteomics/Genomics, University of Toledo Health Science Campus, Toledo, OH 43614, USA b Department of Bioinformatics, Institute of Molecular Genetics, RAS, Moscow 123182, Russia c Section of Medical Genetics and Molecular Medicine, Children's Mercy Hospitals and Clinics and University of Missouri, Kansas City School of Medicine, Kansas City, MO, USA d Department of Medicine, University of Toledo Health Science Campus, Toledo, OH 43614, USA e Dinom LLC, 8/44 Pedagogicheskaya st., Moscow 115404, Russia Received 31 July 2007; received in revised form 19 October 2007; accepted 24 October 2007 Available online 21 November 2007 Received by Takashi Gojobori Abstract Among thousands of non-protein-coding RNAs which have been found in humans, a significant group represents snoRNA molecules that guide other types of RNAs to specific chemical modifications, cleavages, or proper folding. Yet, hundreds of mammalian snoRNAs have unknown function and are referred to as “orphan” molecules. In 2006, for the first time, it was shown that a particular orphan snoRNA (HBII-52) plays an important role in the regulation of alternative splicing of the serotonin receptor gene in humans and other mammals. In order to facilitate the investigation of possible involvement of snoRNAs in the regulation of pre-mRNA processing, we developed a new computational web resource, snoTARGET, which searches for possible guiding sites for snoRNAs among the entire set of human and rodent exonic and intronic sequences.
    [Show full text]
  • Genetic and Genomic Analysis of Hyperlipidemia, Obesity and Diabetes Using (C57BL/6J × TALLYHO/Jngj) F2 Mice
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Nutrition Publications and Other Works Nutrition 12-19-2010 Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P. Stewart Marshall University Hyoung Y. Kim University of Tennessee - Knoxville, [email protected] Arnold M. Saxton University of Tennessee - Knoxville, [email protected] Jung H. Kim Marshall University Follow this and additional works at: https://trace.tennessee.edu/utk_nutrpubs Part of the Animal Sciences Commons, and the Nutrition Commons Recommended Citation BMC Genomics 2010, 11:713 doi:10.1186/1471-2164-11-713 This Article is brought to you for free and open access by the Nutrition at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Nutrition Publications and Other Works by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. Stewart et al. BMC Genomics 2010, 11:713 http://www.biomedcentral.com/1471-2164/11/713 RESEARCH ARTICLE Open Access Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P Stewart1, Hyoung Yon Kim2, Arnold M Saxton3, Jung Han Kim1* Abstract Background: Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/ JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia.
    [Show full text]
  • S41467-020-18249-3.Pdf
    ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.
    [Show full text]
  • Functional Genomics Atlas of Synovial Fibroblasts Defining Rheumatoid Arthritis
    medRxiv preprint doi: https://doi.org/10.1101/2020.12.16.20248230; this version posted December 18, 2020. 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. All rights reserved. No reuse allowed without permission. Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability Xiangyu Ge1*, Mojca Frank-Bertoncelj2*, Kerstin Klein2, Amanda Mcgovern1, Tadeja Kuret2,3, Miranda Houtman2, Blaž Burja2,3, Raphael Micheroli2, Miriam Marks4, Andrew Filer5,6, Christopher D. Buckley5,6,7, Gisela Orozco1, Oliver Distler2, Andrew P Morris1, Paul Martin1, Stephen Eyre1* & Caroline Ospelt2*,# 1Versus Arthritis Centre for Genetics and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK 2Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland 3Department of Rheumatology, University Medical Centre, Ljubljana, Slovenia 4Schulthess Klinik, Zurich, Switzerland 5Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK 6NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK 7Kennedy Institute of Rheumatology, University of Oxford Roosevelt Drive Headington Oxford UK *These authors contributed equally #corresponding author: [email protected] NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2020.12.16.20248230; this version posted December 18, 2020. 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.
    [Show full text]
  • The Landscape of Genomic Imprinting Across Diverse Adult Human Tissues
    Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Research The landscape of genomic imprinting across diverse adult human tissues Yael Baran,1 Meena Subramaniam,2 Anne Biton,2 Taru Tukiainen,3,4 Emily K. Tsang,5,6 Manuel A. Rivas,7 Matti Pirinen,8 Maria Gutierrez-Arcelus,9 Kevin S. Smith,5,10 Kim R. Kukurba,5,10 Rui Zhang,10 Celeste Eng,2 Dara G. Torgerson,2 Cydney Urbanek,11 the GTEx Consortium, Jin Billy Li,10 Jose R. Rodriguez-Santana,12 Esteban G. Burchard,2,13 Max A. Seibold,11,14,15 Daniel G. MacArthur,3,4,16 Stephen B. Montgomery,5,10 Noah A. Zaitlen,2,19 and Tuuli Lappalainen17,18,19 1The Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv 69978, Israel; 2Department of Medicine, University of California San Francisco, San Francisco, California 94158, USA; 3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; 4Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA; 5Department of Pathology, Stanford University, Stanford, California 94305, USA; 6Biomedical Informatics Program, Stanford University, Stanford, California 94305, USA; 7Wellcome Trust Center for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7BN, United Kingdom; 8Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; 9Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland;
    [Show full text]
  • Novel Driver Strength Index Highlights Important Cancer Genes in TCGA Pancanatlas Patients
    medRxiv preprint doi: https://doi.org/10.1101/2021.08.01.21261447; this version posted August 5, 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 . Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients Aleksey V. Belikov*, Danila V. Otnyukov, Alexey D. Vyatkin and Sergey V. Leonov Laboratory of Innovative Medicine, School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow Region, Russia *Corresponding author: [email protected] NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2021.08.01.21261447; this version posted August 5, 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 . Abstract Elucidating crucial driver genes is paramount for understanding the cancer origins and mechanisms of progression, as well as selecting targets for molecular therapy. Cancer genes are usually ranked by the frequency of mutation, which, however, does not necessarily reflect their driver strength. Here we hypothesize that driver strength is higher for genes that are preferentially mutated in patients with few driver mutations overall, because these few mutations should be strong enough to initiate cancer.
    [Show full text]
  • Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement.
    [Show full text]
  • Clinical Validation of the Tempus Xt Next-Generation Targeted Oncology Sequencing Assay
    www.oncotarget.com Oncotarget, 2019, Vol. 10, (No. 24), pp: 2384-2396 Research Paper Clinical validation of the tempus xT next-generation targeted oncology sequencing assay Nike Beaubier1, Robert Tell1, Denise Lau1, Jerod R. Parsons1, Stephen Bush1, Jason Perera1, Shelly Sorrells1, Timothy Baker1, Alan Chang1, Jackson Michuda1, Catherine Iguartua1, Shelley MacNeil1, Kaanan Shah1, Philip Ellis1, Kimberly Yeatts1, Brett Mahon1, Timothy Taxter1, Martin Bontrager1, Aly Khan1, Robert Huether1, Eric Lefkofsky1 and Kevin P. White1 1Tempus Labs Inc., Chicago, IL 60654, USA Correspondence to: Nike Beaubier, email: [email protected] Kevin P. White, email: [email protected] Keywords: tumor profiling, next-generation sequencing assay validation Received: August 03, 2018 Accepted: February 03, 2019 Published: March 22, 2019 Copyright: Beaubier et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT We developed and clinically validated a hybrid capture next generation sequencing assay to detect somatic alterations and microsatellite instability in solid tumors and hematologic malignancies. This targeted oncology assay utilizes tumor- normal matched samples for highly accurate somatic alteration calling and whole transcriptome RNA sequencing for unbiased identification of gene fusion events. The assay was validated with a combination of clinical specimens and cell lines, and recorded a sensitivity of 99.1% for single nucleotide variants, 98.1% for indels, 99.9% for gene rearrangements, 98.4% for copy number variations, and 99.9% for microsatellite instability detection. This assay presents a wide array of data for clinical management and clinical trial enrollment while conserving limited tissue.
    [Show full text]