ADVANCES IN UNDERSTANDING GENETIC CHANGES IN CANCER

Impact on Diagnosis and Treatment Decisions in the 1990s

A Research Briefing from the Division of Health Sciences Policy

INSTITUTE OF MEDICINE

National Academy Press
Washington, D.C.
1992



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Advances in Understanding Genetic Changes in Cancer: Impact on Diagnosis and Treatment Decisions in the 1990s ADVANCES IN UNDERSTANDING GENETIC CHANGES IN CANCER Impact on Diagnosis and Treatment Decisions in the 1990s A Research Briefing from the Division of Health Sciences Policy INSTITUTE OF MEDICINE National Academy Press Washington, D.C. 1992

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Advances in Understanding Genetic Changes in Cancer: Impact on Diagnosis and Treatment Decisions in the 1990s The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under both the Academy’s 1863 Congressional charter responsibility to be an advisor to the federal government, and its own initiative in identifying issues of medical care, research, and education. Research briefings are an important part of the agreement between the Institute of Medicine and the Howard Hughes Medical Institute to initiate a program of studies that is intended to facilitate the translation of discoveries in basic science into advances for health. Of specific interest in the research briefings are the assessment of current knowledge in a particular field of study, identification of promising areas within that field, and recommendations about future research needs in terms of scientific issues. Although occasional recommendations are made regarding research policy, it is not the purpose of these briefings to advocate increases or decreases in current funding levels or to undertake a prioritization or comparative evaluation of other areas of scientific inquiry. The audience for research briefings is quite broad and includes grant administrators and project officers (government and nongovernment), physicians, science policy analysts, congressional staff, scientists, science journalists, and the interested lay public. Research briefing topics are selected by the Institute of Medicine in consultation with its membership, the IOM Council, and the Board on Health Sciences Policy. Library of Congress Catalog Card No. 92-60001 International Standard Book Number 0-309-04688-2 Additional copies of this report are available from: National Academy Press 2101 Constitution Avenue, N.W. Washington, D.C. 20418 S537 Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatlichemuseen in Berlin.

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Advances in Understanding Genetic Changes in Cancer: Impact on Diagnosis and Treatment Decisions in the 1990s PANEL FOR THE RESEARCH BRIEFING ON ADVANCES IN UNDERSTANDING GENETIC CHANGES IN CANCER: IMPACT ON DIAGNOSIS AND TREATMENT DECISIONS IN THE 1990s JANET D. ROWLEY (Co-Chair), Department of Medicine and of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois JEFFREY L. SKLAR (Co-Chair), Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts GARRETT M. BRODEUR, Division of Hematology/Oncology, St. Louis Children's Hospital, St. Louis, Missouri WEBSTER K. CAVENEE, Ludwig Institute-Montreal Branch, Montreal, Quebec, Canada BEVERLY F. EMANUEL, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania STANLEY J. KORSMEYER, Howard Hughes Medical Institute, St. Louis, Missouri DANIEL PINKEL, Division of Molecular Cytometry, University of California at San Francisco, San Francisco, California DENNIS J. SLAMON, Division of Hematology/Oncology, University of California at Los Angeles, Los Angeles, California SANFORD A. STASS, Division of Laboratory Medicine, M.D. Anderson Cancer Center, Houston, Texas LOUIS C. STRONG, Division of Pediatrics, M.D. Anderson Cancer Center, Houston, Texas Rapporteur JON C. ASTER, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts Institute of Medicine Staff DAVID M. TURNER, Project Director, Research Briefing RUTH ELLEN BULGER, Director, Division of Health Sciences Policy SARAH A. ZIELINSKI, Project Assistant RITA T. GIBSON, Administrative Assistant

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Advances in Understanding Genetic Changes in Cancer: Impact on Diagnosis and Treatment Decisions in the 1990s Statement of Purpose Committee for the Research Briefing on Advances in Understanding Genetic Changes in Cancer: Impact on Diagnosis and Treatment Decisions in the 1990s The purpose of this committee was to conduct a research briefing to examine the utilization of genetic techniques for the diagnosis and prognosis of cancer and the impact of this utilization on diagnosis, prognosis, and treatment decisions. Research briefings are sponsored by the Howard Hughes Medical Institute and address three purposes: (1) to highlight a promising and exciting field of medical science; (2) to examine the current status of that field; and (3) to make scientific recommendations about future needs in the field. This research briefing is directed largely toward informing physicians of the rapid advances being made in this field.

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Advances in Understanding Genetic Changes in Cancer: Impact on Diagnosis and Treatment Decisions in the 1990s Contents 1   Introduction   1     Outline of Molecular Genetics   2     Brief Overview of Cancer Genetics   3 2   Testing for Tumor-Specific Genetic Markers   8     Microscopic Detection of Alterations in DNA Structure   9     In Situ Hybridization   12     Ploidy Analysis   15     Techniques for Detecting Changes in DNA Structure at the Submicroscopic Level   16     Southern Blot Hybridization   16     Pulsed-Field Gel Electrophoresis   18     Polymerase Chain Reaction   19     Techniques for Detection of Point Mutations in DNA   21     Techniques Directed at Analysis of RNA   22     Techniques for Analyzing Changes at the Protein Level   23     Immunohistochemistry   23 3   Hematologic Cancer   25     Chronic Myelogenous Leukemia   25     Chronic Lymphocytic Leukemia   32     Acute Lymphocytic Leukemia   32     Acute Myelogenous Leukemia   36     Myelodysplastic Syndromes   38     Lymphoma   39

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Advances in Understanding Genetic Changes in Cancer: Impact on Diagnosis and Treatment Decisions in the 1990s 4   Solid Tumors   45     Chromosomal Aberrations of Diagnostic Importance   47     Chromosomal Aberrations of Prognostic Importance   48     Neuroblastoma   48     Breast Cancer   50     Lung Cancer   52     Other Solid Tumors   53     Genetic Markers of Predisposition to Cancer   53     Retinoblastoma   53     Mapping of Other Cancer Predisposition Loci   55     Li-Fraumeni Syndrome   57     Loss of Heterozygosity in Sporadic Solid Tumors   58     Genetic Changes and Tumor Progression   59     Colorectal Neoplasms   59     Glial Tumors   61     Cancer-Associated Genetic Changes and Environmental Mutagens   62     Viral Markers in Cancer Diagnosis   62 5   Summary and Specific Recommendations   65     Practical Aspects of Genetic Analysis: From Patient to Diagnostic Laboratory   66     The Molecular Diagnostic Laboratory   67     Implications of Commercialization   67     Future Needs   68 6   References   69

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Advances in Understanding Genetic Changes in Cancer: Impact on Diagnosis and Treatment Decisions in the 1990s ADVANCES IN UNDERSTANDING GENETIC CHANGES IN CANCER

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