Cancer Treatment and Research

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1 Cancer Treatment and Research Volume 155 Series Editor Steven T. Rosen For further volumes:

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3 Boris Pasche Editor Cancer Genetics 123

4 Editor Boris Pasche, MD, PhD, FACP The UAB Comprehensive Cancer Center Division of Hematology/Oncology The University of Alabama at Birmingham Birmingham, AL, USA ISSN ISBN e-isbn DOI / Springer New York Dordrecht Heidelberg London Library of Congress Control Number: Springer Science+Business Media, LLC 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (

5 This book is dedicated to Drs. Joan Massagué and Kenneth Offit. Dr. Massagué is an outstanding scientist, mentor, and role model who introduced me to the field of TGF-β signaling and cancer genetics. Dr. Offit is a pioneer in the field of clinical cancer genetics and was instrumental in my career development and progression.

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7 Contents 1 Ethicolegal Aspects of Cancer Genetics... 1 Kenneth Offit and Peter Thom 2 The Influence of Common Polymorphisms on Breast Cancer Diana Eccles and William Tapper 3 Hereditary Diffuse Gastric Cancer Kasmintan Schrader and David Huntsman 4 Genetics and Genomics of Neuroblastoma Mario Capasso and Sharon J. Diskin 5 TGF-β Signaling Alterations and Colon Cancer Naresh Bellam and Boris Pasche Index vii

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9 Contributors Naresh Bellam Division of Hematology/Oncology, Department of Medicine, UAB Comprehensive Cancer Center, The University of Alabama, Birmingham, AL , USA Mario Capasso CEINGE Advanced Biotechnologies, University of Naples Federico II, Naples, Italy Sharon J. Diskin Oncology Division, Center for Childhood Cancer Research, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA Diana Eccles Human Genetics and Cancer Sciences Divisions, School of Medicine, University of Southampton, Southampton University Hospitals NHS Trust, SO16 6YD, UK David Huntsman Department of Pathology and Laboratory Medicine, Vancouver General Hospital, University of British Columbia, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6 Kenneth Offit Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA Boris Pasche Division of Hematology/Oncology, Department of Medicine, UAB Comprehensive Cancer Center, The University of Alabama, Birmingham, AL , USA Kasmintan Schrader Department of Pathology and Laboratory Medicine and Department of Medical Genetics, University of British Columbia, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6 William Tapper Human Genetics and Cancer Sciences Divisions, School of Medicine, University of Southampton, Southampton University Hospitals NHS Trust, SO16 6YD, UK Peter Thom Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA ix

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11 Introduction Boris Pasche Cancer genetics is a rapidly evolving field, which has revolutionized the practice of medicine in the past decade. Genetic testing for several high-penetrance tumor susceptibility genes such as BRCA1, BRCA2, and APC have allowed the identification of individuals at high risk for breast and colon cancers that can be effectively prevented with early screening. Somatically acquired genetic changes such as overexpression of the ERBB2 gene in breast cancer and mutations of the KRAS or BRAF genes in colorectal cancer are observed in a significant fraction of patients. These genetic alterations can be effectively targeted with antibodies such as trastuzumab and cetuximab. Treatment with these genetically targeted agents increases patient survival. Because genetic information allows for the exact identification of individuals, the widespread expansion of genetic testing is potentially fraught with ethical and legal issues. The first chapter of this book, which is written by Drs. Offit and Thom, provides an insightful overview of the ethical aspects of cancer genetics. Systematic studies of common genetic variants are facilitated by the fact that individuals who carry a particular SNP allele at one site often predictably carry specific alleles at other nearby sites. This correlation is known as linkage disequilibrium (LD); a particular combination of alleles along a chromosome is termed a haplotype. The correlations between causal mutations and the haplotypes on which they arose have long served as a tool for human genetic research: first finding an association to a haplotype and then subsequently identifying the causal mutation(s) that it carries. With the sequencing of the human genome and development of high-throughput genomic methods, it has become clear that the human genome generally displays more LD than under simple population genetic models, and that LD is more varied across regions, and more segmentally structured, than had previously been supposed. These observations indicated that LD-based methods would generally have a great value (because nearby SNPs were typically correlated with many of the neighbors), and also that LD relationships would need to be empirically determined across B. Pasche (B) Division of Hematology/Oncology, Department of Medicine, UAB Comprehensive Cancer Center, The University of Alabama, Birmingham, AL , USA boris.pasche@ccc.uab.edu xi

12 xii Introduction the genome by studying polymorphisms at high density in population samples. This has provided the rationale for the development of the International HapMap project ( Novel genotyping technologies combined with the knowledge generated by the HapMap project have provided the necessary tools to interrogate the association of genetic variants from the entire genome with risk for various diseases. The influence of such common polymorphisms on breast cancer, one of the leading causes of cancer death, is thoroughly reviewed in the second chapter written by Drs. Eccles and Tapper. In the third chapter, Drs. Schrader and Huntsman provide the latest genetic knowledge related to gastric cancer and focus on genetic cause, identification, and management of a rare but deadly syndrome, hereditary gastric cancer. Recent advances in cancer genetics are not limited to adult tumors. In the fourth chapter, Drs. Capasso and Diskin provide a timely update on the recent and exciting genetic discoveries related to one of the most common pediatric cancer, neuroblastoma. In the fifth and last chapter, Drs. Bellam and Pasche review the latest discoveries related to constitutively altered TGF-β signaling in colorectal cancer risk, a novel phenotype that may account for a large proportion of colorectal cancers.

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