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Wolfgang A. Schulz Molecular Biology of Human Cancers Second Edition Molecular Biology of Human Cancers Wolfgang A. Schulz Molecular Biology of Human Cancers Second Edition Wolfgang A. Schulz Department of Urology Heinrich Heine University Düsseldorf Düsseldorf, Germany ISBN 978-3-031-16285-5 ISBN 978-3-031-16286-2 (eBook) https://doi.org/10.1007/978-3-031-16286-2 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2007, 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. 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This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Meinen Eltern gewidmet Preface The first edition of this book, written almost two decades ago, developed from a lecture series that I had organized at the Heinrich Heine University Düsseldorf. The book was intended to address in particular advanced students, like PhD students with a background in molecular cell biology or medical doctors taking up molecular cancer research. I have meanwhile learned that the book has also been useful in master courses, especially courses in molecular biomedicine curricula. This second edition has benefitted from lectures in our regular master course on molecular oncology and in our graduate school, the Düsseldorf School of Oncology. I owe to all those that contributed to that course and the lectures. The second edition likewise is primarily directed at advanced students, but it should be accessible to (hopefully many) others as well, with the help of a good textbook on molecular cell biology or human molecular genetics. One criticism on the first edition was that the text appeared very “dense”; that may still be so because I have tried to keep the book (relatively) concise, but I have deconvoluted sentences and clarified explanations. Colored figures in the second edition should also help to make the book more readable. Please see also the following comments on “how to read this book.” I am very grateful to many colleagues that contributed to the second edition by reading drafts of chapters or (valiantly) the entire manuscript, providing comments, figures, or important references. These were especially, at my home institution, Michèle Hoffmann, Gerhard Fritz, Wolfgang Göring, Annemarie Greife, Helmut Hanenberg, Csaba Mahotka, Hans Neubauer, Dieter Niederacher, Günter Niegisch, Julia Reifenberger, Simon Santourlidis, Margaretha Skowron, Rüdiger Sorg, and Nikolas Stoecklein, as well as Nadine Gaisa at the RWTH Aachen, Roman Nawroth at the TU München, Akinori Sato at the National Defense Medical College, Tokorozawa, and Jiři Hatina and his colleagues Vladimir Korinek and Jiři Sramek at the Charles University Prague at Plzen. I would particularly like to acknowledge Rainer Engers, Neuss, for providing a huge selection of photographs for preparing the histology figures and for correcting the according legends. At Springer Nature, I am indebted to Ina Stoeck who kindly guided and advised me dur- ing the process of writing and producing this edition, as well as to Gopalakrishnan Rajesh and the production team. I remain grateful as well to vii viii Preface everybody who contributed to the first edition. As always, I have to thank my wife and family for encouragement and support (as well as patience…). I hope you will find this book informative and useful. Please feel free to send any comments and suggestions for improvement to my e-mail address [email protected]. Duesseldorf, Germany Wolfgang A. Schulz June 2022 How to Read This Book I recommend of course to read this book from front to back—reading one chapter per day, this will take less than a month. If you wish to skip a chapter, I suggest taking a look at its introductory key points to make sure that you will not miss anything that might be important to you. The book is divided into three main parts. Following a general introduction to human cancers in Chap. 1, the first part introduces molecular, genetic, and cellular mechanisms that are relevant to cancer development. The second, central part deals with individual cancers. In this second edition, the most common cancers each have their own chapter. Many additional cancers are treated in specific sections or briefly in boxes. Please consider that while I hope to have included basic information on the etiology, molecular genetics, pathobiology, and the treatment for most cancer types, the aim of the chapters in Part II is not to provide a comprehensive description of each cancer. More importantly, individual cancers rather serve as examples for how some of the mechanisms outlined in the first part operate in real cancers. For instance, carcinogenesis by physical, chemical, and biological agents is described in more detail in the context of skin cancers, bladder and lung cancers, and liver and stomach cancers, respectively. Similarly, the function of specific signal transduction pathways (“cancer pathways”) and processes is treated in more detail in cancer types where they are most relevant. For instance, WNT and TGFβ signaling are taken up again in the colorectal cancer chapter and tumor hypoxia in the chapter on renal cancers; mechanisms of metastasis are described in more detail in the context of prostate cancer. Collectively, Part II should moreover serve to illustrate the diversity of pathogenic mechanisms among human cancers. Part III deals with the applications (envisioned and realized) that originate from the insights into the molecular mechanisms of cancer development and progression. In these chapters, again, no comprehensive description is intended (nor possible), instead, general principles are outlined and instructive examples are discussed in detail. Note that the three-part structure implicates that some topics appear in several places, usually in more depth in later chapters. For instance, some basics of tumor immunology are introduced in Chap. 9, tumor antigens in the context of melanoma in Chap. 12 and tumor immunotherapy in Chap. 23. Crossreferences throughout the book refer back to figures, sections or chapters where terms and concepts were introduced, or refer forward to places where they are going to be treated in more detail. ix x How to Read This Book The general aim of this textbook is to make readers familiar with the most relevant genes and proteins as well as molecular and cellular mechanisms implicated in human cancers. I also aim at introducing and discussing many of the current concepts underlying molecular cancer research and its clinical applications. These concepts are crucial for cancer research and its “translation” to clinical applications, but they need to be critically considered and continuously refined. Each chapter is followed by a list of articles for further reading; these are mostly recent review articles, but some original papers are included, for example, on the comprehensive characterization of genomic alterations in specific cancers. You will find that this textbook does not treat the many different ingenious techniques and the often elegant (and usually laborious...) experiments that underlie our knowledge on cancer molecular biology in any appropriate detail. Doing that would have required a different kind of approach (and resulted in a very different and much bigger book); moreover, in molecular biology research and its applications, techniques change very rapidly. The cited reviews in each chapter ought however provide more information on these aspects. One important disclaimer: This is not a textbook of medical oncology. Therefore, mention of diagnostic and therapeutic procedures does not impli- cate that they are recommended (or not) by the author or publisher. Finally, note that names of individual human proteins (but not protein classes) are capitalized throughout the text. Gene names are italicized. Gene and protein names (with aliases) can be found at www.genecards.org and detailed descriptions of hereditary syndromes at www.omim.org. An index of genes and protein is provided at the end of the book; for genes and proteins mentioned frequently, the most pertinent section is indicated. A list of other abbreviations follows below. Contents Part I Molecules, Genes, Cells, and Mechanisms 1 An Introduction to Human Cancers . . . . . . . . . . . . . . . . . . . . . . . 3 1.1 A n Overview of the Cancer Problem . . . . . . . . . . . . . . . . . . . . 4 1.2 C auses of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1.3 C haracteristic Properties of Cancers and Cancer Cells . . . . . . 13 1.4 M etabolic Changes in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.5 C haracterization and Classification of Cancers in The Clinic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 1.6 C ancer Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 2 Cancer Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.1 C ancer as a Genetic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 30 2.2 G enetic Alterations in Cancers . . . . . . . . . . . . . . . . . . . . . . . . . 31 2.3 I nherited Predisposition to Cancer . . . . . . . . . . . . . . . . . . . . . . 39 2.4 C ancer Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 2.5 A ccumulation of Genetic and Epigenetic Changes in Human Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 3 DNA Damage and DNA Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 3.1 D NA Damage and Repair: An Overview . . . . . . . . . . . . . . . . . 52 3.2 D NA Mismatch Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 3.3 N ucleotide Excision Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 3.4 D NA Strand Break Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 3.5 D NA Inter-Strand Crosslink Repair . . . . . . . . . . . . . . . . . . . . . 67 3.6 D eficiencies in DNA Repair and Cancer Susceptibility . . . . . 69 3.7 C ell Protection Mechanisms in Cancer . . . . . . . . . . . . . . . . . . 70 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 4 Oncogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 4.1 R etroviral Oncogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 4.2 S low-Acting Transforming Retroviruses . . . . . . . . . . . . . . . . . 79 4.3 I dentification of Human Oncogenes . . . . . . . . . . . . . . . . . . . . 82 4.4 F unctions of Human Oncogenes: Receptor Tyrosine Kinases and the MAPK Pathway . . . . . . . . . . . . . . . . . . . . . . . 87 xi