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Principles of Molecular Pathology PrinciplesPrinciples ofof MolecularMolecular PathologyPathology Anthony A. Killeen PRINCIPLES OF MOLECULAR PATHOLOGY PRINCIPLES OF MOLECULAR PATHOLOGY By ANTHONY A. KILLEEN, MB, BCh, PhD Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN © 2004 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 www.humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. Production Editor: Tracy Catanese. Cover Illustrations: Figures 23 and 25A–D from Chapter 4, “Methods in Molecular Pathology”; Figure 5 from Chapter 3, “Mutation”; and Figure 9 from Chapter 2, “Genetic Inheritance.” Cover design by Patricia F. Cleary. This publication is printed on acid-free paper. ∞ ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials. For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-8341; E-mail: [email protected] or visit our website: http://www.humanapress.com Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $25.00 per copy is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [1-58829-085-9/04 $25.00]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 1-59259-431-X (e-book) Library of Congress Cataloging-in-Publication Data Killeen, Anthony A. Principles of molecular pathology / by Anthony A. Killeen. p. cm. Includes bibliographical references and index. ISBN 1-58829-085-9 (alk. paper) 1. Pathology, Molecular. 2. Genetic disorders. I. Title. RB113.K47 2003 616.07’56--dc21 2003041737 DEDICATION In memoriam parentium, Professor James Francis and Joyce Killeen. v PREFACE Principles of Molecular Pathology provides a comprehensive, but concise introduction to this rapidly growing subject. It will be useful to a wide readership including residents and fellows in laboratory medicine and pathology, practicing pathologists who have not had a formal exposure to this relatively new field, and our medical and scientific colleagues in related laboratory and clinical disciplines. Only a few years ago, experts debated whether molecular pathology was a bona fide academic discipline, or merely the application of new laboratory tech- niques that would find their roles in existing areas of the clinical laboratories. Now it is clear that this field is far more than just a set of novel techniques. Molecular pathology has a grand theme, and that theme is the study of genetic mutations, both inherited and acquired, and their effects on the structure and function of the cell. Within this theme, molecular pathology brings together concepts from molecular biology, genetics, and traditional pathology to provide new insights into human diseases, new ways of classifying certain types of dis- eases, and the technologies to provide new diagnostic and prognostic informa- tion. There is no doubt that the practice of laboratory medicine and pathology will be significantly altered by the principles and laboratory methods of molecular pathology. The topics in Principles of Molecular Pathology were chosen to provide a broad overview of the field. Basic concepts of human molecular biology and genetics are followed by a description of the most commonly used analytical methods. This background is followed by a discussion of the acquired genetic abnormalities that underlie human malignancies. Chapters on pharmacogenetics and identity testing emphasize the growing importance of these areas in clinical practice. The application of molecular methods to the detection of microbial pathogens has assumed an essential role in clinical laboratory practice, and this important area is illustrated using common viral infections as examples. I hope that Principles of Molecular Pathology will stimulate interest in this exciting field. I welcome comments from readers at [email protected]. Acknowledgments First and foremost, I thank my wife, Randee, for her love and support, and for her patience during the course of my writing this book. It would never have been completed without the time she afforded me to write. Our children, Olivia and Trevor, were a constant source of energy and enthusiasm during this project. I acknowledge with gratitude the excellent support of my colleagues at the University of Minnesota and my former colleagues at the University of Michi- vii viii Preface gan. Several have read and commented on chapters, including Matt Bower, Charlotte Brown, Michelle Dolan, Betsy Hirsch, Mark Linder, Elizabeth Petty, and Rima Tinawi-Aljundi. I thank them sincerely for their suggestions. Anthony A. Killeen CONTENTS Preface ............................................................................................... vii 1 Basic Concepts in Molecular Pathology..................................... 1 2 Genetic Inheritance ...................................................................31 3 Mutation ....................................................................................57 4 Methods in Molecular Pathology..............................................89 5 Inherited Disorders ..................................................................141 6 Molecular Origins of Cancer ..................................................185 7 Familial Cancer Syndromes ....................................................211 8 Molecular Pathology of Hematological Malignancies ...........239 9 Pharmacogenetics .....................................................................279 10 Identity Testing .......................................................................297 11 Molecular Diagnoses of Human Immunodeficiency Virus and Hepatitis C Virus ...........................................309 Index .................................................................................................327 ix 1 Basic Concepts in Molecular Pathology BASIC TERMINOLOGY Human diseases that have a genetic basis, whether hereditary or acquired, arise from changes in the sequence or pattern of expres- sion of genes. A gene, which is the unit of heredity, is a piece of DNA that encodes a protein or RNA. The position at which a given gene is found on a chromosome is known as its locus. Sequence variants of a gene are known as alleles, and the most common func- tional allele at a locus is known as the wild-type allele. Changes in the sequence of DNA are known as mutations. In genetic use, the term mutation does not necessarily mean that the effect of the change in sequence is deleterious to the organism. By definition, a sequence change that is present in at least 1% of the population is known as a polymorphism. In the haploid cell, the human genome is composed of approxi- mately 3 × 109 bp of DNA, the sequence of which has largely been determined through the efforts of the public and commercial human genome projects (1,2). Most of the genome is located in the nucleus, but mitochondria also contain a small genome that is approximately 16.5 kb in length. The set of genes that is expressed in a cell deter- mines the structure and functions of the cell. STRUCTURE OF NUCLEIC ACIDS Both DNA and RNA are polymers composed of repeating units of sugars (deoxyribose or ribose, respectively) with attached bases. The sugars are joined by phosphodiester linkages between the 3′ carbon of one sugar and the 5′ carbon of the next sugar in the poly- mer (Fig. 1). A strand of DNA or RNA therefore has polarity: the end with the terminal 5′-carbon is known as the 5′ end,
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