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Cancer Genomics From Bench to Personalized Medicine http://store.elsevier.com/product.jsp?&isbn=9780123969675 Cancer Genomics: From Bench to Personalized Medicine Graham Dellaire, Jason N. Berman and Robert J. Arceci, Editors Resources available: • All figures from the book available as both Power Point slides and .jpeg files • Links to web sites carefully chosen to supplement the content of the textbook • Contact the editors with questions and/or suggestions Cancer Genomics From Bench to Personalized Medicine Edited by Graham Dellaire, Ph.D. Departments of Pathology and Biochemistry & Molecular Biology Dalhousie University, Halifax, Canada Jason. N. Berman, M.D., FRCPC, FAAP IWK Health Centre, Departments of Pediatrics, Pathology and Microbiology and Immunology Dalhousie University, Halifax, Canada Robert J. Arceci, M.D., Ph.D. The Ron Matricaria Institute of Molecular Medicine at Phoenix Childrens Hospital, Department of Child Health, University of Arizona, College of Medicine, Phoenix, USA AMSTERDAM• BOSTON• HEIDELBERG• LONDON NEW YORK• OXFORD• PARIS• SAN DIEGO SAN FRANCISCO• SINGAPORE• SYDNEY• TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 32 Jamestown Road, London NW1 7BY, UK 225 Wyman Street, Waltham, MA 02451, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA Copyright r 2014 Elsevier Inc. All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher. Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (144) (0) 1865 843830; fax (144) (0) 1865 853333; email: mailto: This book is dedicated to the patients and their families past and future who have both inspired and will one day benefit from the great advancements in cancer genomics and to our own families for their ongoing patience and support of this project. List of Contributors Kenneth C. Anderson Department of Medical Hye-Jung E. Chun British Columbia Cancer Agency, Oncology, Jerome Lipper Multiple Myeloma Center, Vancouver, BC, Canada; Canada’s Michael Smith Dana-Farber Cancer Institute and Department of Genome Sciences Centre, Vancouver, BC, Canada Medicine, Harvard Medical School, Boston, MA, USA Francesca Cottini Department of Medical Oncology, Samuel A. Aparicio British Columbia Cancer Agency, Jerome Lipper Multiple Myeloma Center, Dana-Farber Vancouver, BC, Canada; Department of Pathology and Cancer Institute and Department of Medicine, Harvard Laboratory Medicine, University of British Columbia, Medical School, Boston, MA, USA Vancouver, BC, Canada; Molecular Oncology, British Janet E. Dancey Ontario Institute for Cancer Research, Columbia Cancer Research Centre, Vancouver, BC, Toronto, ON; NCIC Clinical Trials Group, Queen’s Canada University, Kingston, ON, Canada Robert J. Arceci Children’s Center for Cancer and Blood Graham Dellaire Departments of Pathology and Disorders, Hematology/Oncology and The Ron Matricaria Biochemistry & Molecular Biology, Dalhousie Institute of Molecular Medicine, Phoenix Children’s University, Halifax, NS, Canada Hospital, Department of Child Health, University of Amal M. EL-Naggar Department of Molecular Arizona, College of Medicine, Phoenix, AZ, USA Oncology, BC Cancer Research Center, Vancouver, BC; Alejandro Berlin Departments of Radiation Oncology Department of Pathology and Laboratory Medicine, and Medical Biophysics, University of Toronto, University of British Columbia, Vancouver, BC, Canada Toronto, ON, Canada; Ontario Cancer Institute and Conrad V. Fernandez Departments of Pediatrics and Princess Margaret Cancer Center (University Health Bioethics, Head, Division of Pediatric Hematology/ Network), Toronto, ON, Canada Oncology, Dalhousie University and IWK Health Centre, Jason N. Berman Departments of Pediatrics, Halifax, NS, Canada Microbiology and Immunology, and Pathology, Michael Fraser Ontario Cancer Institute and Princess Dalhousie University and IWK Health Centre, Halifax, Margaret Cancer Center (University Health Network), NS, Canada Toronto, ON, Canada Maria Grazia Borrello Molecular Mechanisms Unit, Daniel Gaston Department of Pathology, Dalhousie Department of Experimental Oncology and Molecular University, Halifax, NS, Canada Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Carman Giacomantonio Departments of Pathology and Surgery, Dalhousie University, Halifax, NS, Canada Robert G. Bristow Ontario Cancer Institute and Princess Margaret Cancer Center (University Health Angela Greco Molecular Mechanisms Unit, Network), Toronto, ON, Canada; Departments of Department of Experimental Oncology and Molecular Radiation Oncology and Medical Biophysics, Medicine, Fondazione IRCCS Istituto Nazionale dei University of Toronto, Toronto, ON, Canada Tumori, Milan, Italy Moamen Bydoun Department of Pathology, Dalhousie Erin Hedlund Computational Biology Department, University, Halifax, NS, Canada St Jude Children’s Research Hospital Memphis, TN, USA George A. Calin Department of Experimental Matthew Herder Health Law Institute, Faculties of Therapeutics and Leukemia, The University of Texas Medicine and Law, Dalhousie University, Halifax, NS, MD Anderson Cancer Center, Houston, TX, USA Canada Priscilla P.L. Chiu Department of Surgery, The Peter Hohenstein The Roslin Institute, University of Hospital for Sick Children, Toronto, ON, Canada Edinburgh, Easter Bush Campus, Midlothian, UK xiii xiv List of Contributors Meredith S. Irwin Department of Paediatrics, Hospital Marco A. Marra British Columbia Cancer Agency, for Sick Children and University of Toronto, Toronto, Vancouver, BC, Canada; Canada’s Michael Smith ON, Canada Genome Sciences Centre, Vancouver, BC, Canada; Department of Medical Genetics, University of British Steven J.M. Jones Canada’s Michael Smith Genome Columbia, Vancouver, BC, Canada Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada Anne-Marie Mes-Masson Universite´ de Montre´al, Department of Medicine, Montreal, QC, Canada; Katayoon Kasaian Canada’s Michael Smith Genome Centre hospitalier de l’Universite´ de Montre´al, Institut Sciences Centre, British Columbia Cancer Agency, du Cancer de Montre´al, Montreal, QC, Canada Vancouver, BC, Canada Soheil Meshinchi Clinical Research Division, Fred Javed Khan Oncogenomics Section, Pediatric Hutchinson Cancer Research Center, Department of Oncology Branch, Advanced Technology Center, Pediatrics, University of Washington School of Medicine, National Cancer Institute, Bethesda, MD, USA Seattle, WA, USA Jaswinder Khattra British Columbia Cancer Agency, Claudia Miranda Molecular Mechanisms Unit, Vancouver, BC, Canada; Department of Pathology and Department of Experimental Oncology and Molecular Laboratory Medicine, University of British Columbia, Medicine, Fondazione IRCCS Istituto Nazionale dei Vancouver, BC, Canada; Molecular Oncology, British Tumori, Milan, Italy Columbia Cancer Research Centre, Vancouver, BC, Canada Stephen B. Montgomery Departments of Pathology and Genetics, Stanford University, Stanford, CA, USA Martin Krzywinski British Columbia Cancer Agency, Vancouver, BC, Canada; Canada’s Michael Smith Daniel A. Morgenstern Department of Paediatrics, Genome Sciences Centre, Vancouver, BC, Canada Hospital for Sick Children and University of Toronto, Toronto, ON, Canada Ce´cile Le Page Centre hospitalier de l’Universite´ de Montre´al, Institut du Cancer de Montre´al, Montreal, Ryan D. Morin Department of Molecular Biology and QC, Canada Biochemistry, Simon Fraser University, Burnaby, BC, Canada Gabriel Leprivier Department of Molecular Oncology, BC Cancer Research Center, Vancouver, BC; Department Veronique Ouellet Centre de Recherche du Centre hos- of Pathology and Laboratory Medicine, University of pitalier de l’Universite´ de Montre´al, Montreal, QC, British Columbia, Vancouver, BC, Canada Canada Yvonne Y. Li Canada’s Michael Smith Genome Louise Parker Departments of Medicine and Sciences Centre, British Columbia Cancer Agency, Pediatrics, Dalhousie University, Halifax, NS, Canada Vancouver, BC, Canada Matthew Parker Computational Biology Department, Hui Ling Department of Experimental Therapeutics St Jude Children’s Research Hospital Memphis, TN, and Leukemia, The University of Texas MD Anderson USA Cancer Center, Houston, TX, USA Elizabeth J. Perlman Ann & Robert H. Lurie Children’s Anthony M. Magliocco H. Lee Moffitt Cancer Center Hospital of Chicago, Northwestern University Feinberg and Research Institute, Tampa, FL, USA School of Medicine, Chicago, IL, USA David Malkin Division of Hematology/Oncology, Marco A. Pierotti Scientific Directorate, Fondazione The Hospital for Sick Children and Department of IRCCS Istituto Nazionale dei Tumori, Milan, Italy Pediatrics, University of Toronto, Toronto, ON, Shahrad Rod Rassekh Child and Family Research Canada Institute, British Columbia’s Children’s Hospital, Branavan Manoranjan McMaster Stem Cell and Vancouver, BC, Canada; Department of Pediatrics, Cancer Research Institute, McMaster University, Division of Pediatric Hematology/Oncology/BMT, Hamilton, ON, Canada; Michael G. DeGroote School University of British Columbia, Vancouver, BC, of Medicine, McMaster University, Hamilton, ON, Canada Canada Colin J.D. Ross Child and Family Research Institute, Paola Marcato Department of Pathology, Dalhousie British Columbia’s Children’s Hospital, Vancouver, University, Halifax, NS, Canada BC, Canada; Department of Pediatrics, Division of List of Contributors xv Translational Therapeutics, University of British Chitra Venugopal McMaster Stem Cell and Cancer Columbia, Vancouver, BC, Canada; Centre for Research Institute, McMaster University, Hamilton, Molecular Medicine and Therapeutics, University of ON, Canada British Columbia, Vancouver, BC, Canada Parvez Vora McMaster Stem Cell and Cancer Fred Saad Department of Surgery, Centre hospitalier Research Institute, McMaster University, Hamilton, de l’Universite´ de Montre´al, Montreal, QC, Canada; ON, Canada Montreal Cancer Institute, Montreal, QC, Canada Jun S. Wei Oncogenomics Section, Pediatric Oncology Sheila K. Singh McMaster Stem Cell and Cancer Branch, Advanced Technology Center, National Research Institute, McMaster University, Hamilton, Cancer Institute, Bethesda, MD, USA ON, Canada; Michael G. DeGroote School of Zhaolin Xu Department of Pathology, Dalhousie Medicine, McMaster University, Hamilton, ON, University and Queen Elizabeth II Health Sciences Canada; Surgery, Faculty of Health Sciences, Centre, Halifax, NS, Canada McMaster University, Hamilton, ON, Canada Jinghui Zhang Computational Biology Department, Poul H. Sorensen Department of Molecular Oncology, St Jude Children’s Research Hospital Memphis, TN, BC Cancer Research Center, Vancouver, BC; Department USA of Pathology and Laboratory Medicine, University of Shile Zhang Oncogenomics Section, Pediatric British Columbia, Vancouver, BC, Canada Oncology Branch, Advanced Technology Center, Giovanni Tonon Division of Molecular Oncology, National Cancer Institute, Bethesda, MD, USA; Functional Genomics of Cancer Unit, San Raffaele Program in Bioinformatics, Boston University, Boston, Scientific Institute, Milan, Italy MA, USA Chapter 1 Cancer Genomics Historical Perspective and Current Challenges of Cancer Genomics Graham Dellaire1 1Departments of Pathology and Biochemistry & Molecular Biology, Robert J. Arceci2 2D Cahlhiloduresine’sUnCiveenrtseirty,foHraliCfaaxn,cNerS, aCnadnaBdalood Disorders, Hematology/ Oncology and The Ron Matricaria Institute of Molecular Medicine, Phoenix Children’s Hospital, Department of Child Health, University of Arizona, College of Medicine, Phoenix, AZ, USA Contents A Historical Perspective on the Development of Cancer Genomics 4 Current and Future Challenges 7 Glossary 8 Abbreviations 8 References 8 Cancer Genomics. DOI: http://dx.doi.org/10.1016/B978-0-12-396967-5.00001-3 © 2014 Elsevier Inc. All rights reserved. 3 4 PART | 1 Introduction the 20th century was ushered in by a set of remarkable Key Concepts observations in cancer biology that were made before the ● Advances in nucleic acid sequencing technology have discovery of DNA. These included the theories of Rous had a profound impact on the field of cancer genomics regarding the potential viral origin of some cancers in and have enabled the interrogation of the genetic basis 1910, derived from his work on avian sarcomas, and the of cancer at the single nucleotide level concept of the somatic mutation theory of cancer by ● Cancer genomics has provided a detailed view of the Boveri in 1914 that stemmed from his work on polysper- complexity of the cancer genome, including the mic development in invertebrates [5,6]. extraordinary ability to sustain and thrive on alterations While not necessarily providing a deeper understand- of DNA ing of the mechanisms of carcinogenesis, the first half of ● Translating cancer genomics into clinically real time the 20th century in many ways broke open the gates of and actionable personalized medicine is beginning to cancer treatment. After being commissioned by the US be tested, although significant advances in the speed of providing molecular data, analysis, utilizing government to understand the physiological consequences combination targeted agents and understanding clinical of nitrogen mustard gas used in warfare, Louis Goodman response or no response will require new generations of and Alfred Gilman recognized the key bone marrow tox- technology and bioinformatic tools icity of this agent and subsequently introduced its intrave- nous use for the treatment of lymphoid malignancies in 1946 [7]. Soon afterward in 1948, the antimetabolite ami- nopterin was used to treat several children with acute lymphoblastic leukemia by Farber and colleagues, a treat- ment built on the work of the chemist Subbarao [8]. A HISTORICAL PERSPECTIVE ON THE A decade later, in 1958, Hertz, Li and colleagues reported DEVELOPMENT OF CANCER GENOMICS the first cure of a metastatic tumor, namely a gestational- Several hundred years BC, Hippocrates is attributed with related choriocarcinoma, with another antimetabolite, providing us with the term “carcinoma” and thus “can- methotrexate [9]. cer”, originating possibly from the image of finger-like However, despite such encouraging forays into treat- extensions (veins) from a tumorous (main body of the ing patients, few cures were achievable with surgery, tumor) breast lesion that shared resemblance to the shape radiation therapy and chemotherapy. In this regard, the of a crab. Around 400 years later, the Roman physician extraordinary efforts of Ms Mary Lasker following her Celsus translated the Greek (karkinos) into the Latin word husband’s death from cancer should not go unmentioned. for crab, which led to the term “cancer” [1,2]. A relative Through her efforts and the Citizens Committee for the late-comer to this nomenclature narrative, in 168 BC, Conquest of Cancer through the 1960s, they challenged Galen introduced the terms “oncos”, meaning “swelling” government, physicians and scientists to push forth with a to describe tumors, leading to the term defining the field “War on Cancer” [10 12]. And this was in spite of a sig- of oncology [3,4]. nificant number of naysayers who had concluded in vari- The next 2000 years witnessed several key events that ous publications that we knew enough to cure cancer and helped to refine further the still ongoing main areas of all that was needed was to translate the knowledge that cancer investigation and treatment. Maimonides in AD was available at the time. Such a lack of vision was 1190 appears to have been the first to document surgi- thankfully thwarted by those who propitiously concluded cally removing tumors [3]. The recognition of cancer that only through scientific discovery and its ongoing clustering in distinct populations was introduced in 1713 application would improvements in cancer outcomes with Razmazzini’s observation of the low cervical but occur. In 1971, the US National Cancer Act was passed high breast cancer incidence in nuns [2]. The observation by Congress and then President Nixon signed it into law that environmental and occupational exposures can be within 2 weeks, an astonishingly rapid accomplishment associated with increased incidence of specific cancers on the part of government and one that should inform cur- also became evident. In the first half of the 1800s, rent, often stalled efforts [10 13]. The consequences of Recmier appears to have reignited the flare for nomencla- the above investment, along with other efforts across the ture by writing about “metastasis” in 1829 to describe the globe [14], led to an infusion of intellectual engagement movement of some cancers to different parts of the body and financial support for conquering cancer. The results [3]. Muller’s notes on the cellular origin of cancer also in included the establishment of clinical trial groups, com- 1838, and Paget’s subsequent “seed and soil” hypothesis prehensive cancer centers, an explosion of new antican- over 50 years later in 1889, established the cognitive par- cer agents from the lab and from nature, and the adigm for the cell biological basis for cancer and the con- beginning of work focused on the biological understand- cept of microenvironmental niches [2,3]. The first half of ing of cancer. This latter work built of course on the

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