Principles of cancer genetics

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Preface to the Third Edition Contents 1: The Genetic Basis of Cancer The Cancer Gene Theory Cancers Are Invasive Tumors Cancer Is a Unique Type of Genetic Disease What Are Cancer Genes and How Are They Acquired? Mutations Alter the Human Genome Genes and Mutations Single Nucleotide Substitutions Gene Silencing Is Marked by Cytosine Methylation: Epigenetics Environmental Mutagens, Mutations, and Cancer Inflammation Promotes the Propagation of Cancer Genes The Immune System Restrains Tumor Growth Stem Cells, Darwinian Selection, and the Clonal Evolution of Cancers Selective Pressure and Adaptation: Hypoxia and Altered Metabolism Multiple Somatic Mutations Punctuate Clonal Evolution Tumor Growth Leads to Cellular Heterogeneity Tumors Are Distinguished by Their Spectrum of Driver Gene Mutations and Passenger Gene Mutations Colorectal Cancer: A Model for Understanding the Step-Wise Process of Tumorigenesis Do Cancer Cells Divide More Rapidly Than Normal Cells? Germline Cancer Genes Allow Neoplasia to Bypass Steps in Clonal Evolution Cancer Syndromes Reveal Rate-Limiting Steps in Tumorigenesis The Etiologic Triad: Heredity, the Environment, and Stem Cell Division Understanding Cancer Genetics Chapter highlights Further Reading 2: Oncogenes What Is an Oncogene? The Discovery of Transmissible Cancer Genes Viral Oncogenes Are Derived from the Host Genome The Search for Activated Oncogenes: The RAS Gene Family Complex Genomic Rearrangements: The MYC Gene Family Proto-oncogene Activation by Gene Amplification Proto-oncogenes Can Be Activated by Chromosomal Translocation Chromosomal Translocations in Liquid Tumors Chronic Myeloid Leukemia and the Philadelphia Chromosome Oncogenic Activation of Transcription Factors in Prostate Cancer and Ewing´s Sarcoma Oncogene Discovery in the Genomic Era: Mutations in PIK3CA Selection of Tumor-Associated Mutations Multiple Modes of Proto-oncogene Activation Oncogenes Are Dominant Cancer Genes Germline Mutations in RET and MET Confer Cancer Predisposition Proto-oncogene Activation and Tumorigenesis Chapter Highlights Further Reading 3: Tumor Suppressor Genes What Is a Tumor Suppressor Gene? The Discovery of Recessive Cancer Phenotypes Retinoblastoma and Knudson´s Two-Hit Hypothesis Chromosomal Localization of the Retinoblastoma Locus The Mapping and Cloning of the Retinoblastoma Gene Tumor Suppressor Gene Inactivation: The Second ``Hit´´ and Loss of Heterozygosity Recessive Genes, Dominant Traits APC Inactivation in Inherited and Sporadic Colorectal Cancers TP53 Is Frequently Inactivated During Tumorigenesis Functional Inactivation of p53: Tumor Suppressor Genes and Oncogenes Interact Mutant TP53 in the Germline: Li Fraumeni Syndrome Gains-of-Function Caused by Cancer-Associated Mutations in TP53 Cancer Predisposition: Allelic Penetrance, Relative Risk and the Odds Ratio Breast Cancer Susceptibility: BRCA1 and BRCA2 Genetic Losses on Chromosome 9: CDKN2A Complexity at CDKN2A: Neighboring and Overlapping Genes Genetic Losses on Chromosome 10: PTEN SMAD4 and the Maintenance of Stromal Architecture Two Distinct Genes Cause Neurofibromatosis Patched Proteins Regulate Developmental Morphogenesis von Hippel-Lindau Disease NOTCH1: Tumor Suppressor Gene or Oncogene? Multiple Endocrine Neoplasia Type 1 Most Tumor Suppressor Genes Are Tissue-Specific Modeling Cancer Syndromes in Mice Genetic Variation and Germline Cancer Genes Tumor Suppressor Gene Inactivation During Colorectal Tumorigenesis Inherited Tumor Suppressor Gene Mutations: Gatekeepers and Landscapers Maintaining the Genome: Caretakers Chapter Highlights Further Reading 4: Genetic Instability and Cancer What Is Genetic Instability? The Majority of Cancer Cells Are Aneuploid Aneuploid Cancer Cells Exhibit Chromosome Instability Chromosome Instability Arises Early in Colorectal Tumorigenesis Chromosomal Instability Accelerates Clonal Evolution Aneuploidy Can Result from Mutations that Directly Impact Mitosis STAG2 and the Cohesion of Sister Chromatids Other Genetic and Epigenetic Causes of Aneuploidy Transition from Tetraploidy to Aneuploidy during Tumorigenesis Multiple Forms of Genetic Instability in Cancer Defects in Mismatch Repair Cause Hereditary Nonpolyposis Colorectal Cancer Mismatch Repair-Deficient Cancers Have a Distinct Spectrum of Mutations Defects in Nucleotide Excision Repair Cause Xeroderma Pigmentosum NER Syndromes: Clinical Heterogeneity and Pleiotropy DNA Repair Defects and Mutagens Define Two Steps Towards Genetic Instability Defects in DNA Crosslink Repair Cause Fanconi Anemia A Defect in DNA Double Strand Break Responses Causes Ataxia-Telangiectasia A Unique Form of Genetic Instability Underlies Bloom Syndrome Aging and Cancer: Insights from the Progeroid Syndromes Instability at the End: Telomeres and Telomerase Overview: Genes and Genetic Stability Chapter Highlights Further Reading 5: Cancer Genomes Discovering the Genetic Basis of Cancer: From Genes to Genomes What Types of Genetic Alterations Are Found in Tumor Cells? How Many Genes Are Mutated in the Various Types of Cancer? What Is the Significance of the Mutations that Are Found in Cancers? When Do Cancer-Associated Mutations Occur? How Many Different Cancer Genes Are There? How Many Cancer Genes Are Required for the Development of Cancer? Cancer Genetics Shapes our Understanding of Metastasis Tumors Are Genetically Heterogeneous Beyond the Exome: The ``Dark Matter´´ of the Cancer Genome Chapter Highlights Further Reading 6: Cancer Gene Pathways What Are Cancer Gene Pathways? Cellular Pathways Are Defined by Protein-Protein Interactions Individual Biochemical Reactions, Multistep Pathways, and Networks Protein Phosphorylation Is a Common Regulatory Mechanism Signals from the Cell Surface: Protein Tyrosine Kinases Membrane-Associated GTPases: The RAS Pathway An Intracellular Kinase Cascade: The MAPK Pathway Genetic Alterations of the RAS Pathway in Cancer Membrane-Associated Lipid Phosphorylation: The PI3K/AKT Pathway Control of Cell Growth and Energetics: The mTOR Pathway Genetic Alterations in the PI3K/AKT and mTOR Pathways Define Roles in Cell Survival The STAT Pathway Transmits Cytokine Signals to the Cell Nucleus Morphogenesis and Cancer: The WNT/APC Pathway Dysregulation of the WNT/APC Pathway in Cancers Notch Signaling Mediates Cell-to-Cell Communication Morphogenesis and Cancer: The Hedgehog Pathway TGF-β/SMAD Signaling Maintains Adult Tissue Homeostasis MYC Is a Downstream Effector of Multiple Cancer Gene Pathways P53 Activation Is Triggered by Damaged or Incompletely Replicated Chromosomes P53 Is Controlled by Protein Kinases Encoded by Tumor Suppressor Genes P53 Induces the Transcription of Genes That Suppress Cancer Phenotypes Feedback Loops Dynamically Control p53 Abundance The DNA Damage Signaling Network Activates Interconnected Repair Pathways Inactivation of the Pathways to Apoptosis in Cancer RB1 and the Regulation of the Cell Cycle Several Cancer Gene Pathways Converge on Cell Cycle Regulators Many Cancer Cells Are Cell Cycle Checkpoint Deficient Chromatin Modification Is Recurrently Altered in Many Types of Cancer Putting Together the Puzzle Chapter Highlights Further Reading 7: Cancer and the Immune System Cancer Cells Express Unique Antigens Tissue Homeostasis Requires Active Surveillance by the Immune System Understanding Immune Surveillance: The Innate and Adaptive Immune Responses to Influenza Activation of Immune Signaling by Cytosolic DNA: The cGAS-STING Pathway Tumorigenesis Is Suppressed by Innate and Adaptive Immune Mechanisms The Seed and the Soil: Tumor Cells Shape Their Microenvironment Dynamic Interactions Between Evolving Tumors and the Immune System: Immunoediting Immunoediting During the Evolution of Multiple Myeloma Immune Checkpoints Restrain T-Cell Function Cancer Cells Activate Immune Checkpoints by Upregulating PD-L1 Tumors Produce Immunomodulatory Metabolites from Tryptophan Immune Tolerance in Sun-Exposed Skin Perspective: A Precarious Balance Chapter Highlights Further Reading 8: Common Cancers and Their Genetic Alterations Cancer Genes Cause Diverse Diseases Cancer Incidence, Prevalence, and Mortality Lung Cancer Prostate Cancer Breast Cancer Colorectal Cancer Endometrial Cancer Melanoma of the Skin Bladder Cancer Lymphoma Cancers in the Kidney Thyroid Cancer Leukemia Cancer in the Pancreas Ovarian Cancer Cancers of the Oral Cavity and Pharynx Liver Cancer Cancer of the Uterine Cervix Stomach Cancer Brain Tumors The Global Burden of Cancer in 2040 Chapter Highlights Further Reading 9: Cancer Detection and Prognostication The Acquisition of DNA Sequence Data Capturing the Complexity of Heterogeneous DNA Samples with Digital PCR Next-Generation Sequencing Mines the Full Information Content of DNA Samples Single-Molecule DNA Sequencing The Applications of Genetic Data Decoding the Elements of Cancer Risk Identifying Carriers of Germline Cancer Genes Biomarkers Facilitate the Detection of Early Stage Malignancies Cancer Genes as Biomarkers Liquid Biopsy Is a Tool for Disease Management Mining the Information Content of Samples Obtained During Routine Screens Cancer Genes Are Versatile Biomarkers for Diagnosis, Prognosis, and Recurrence Assessing the T-Cell Response to Tumor Cells Incorporating Genetic Analysis into Routine Preventive Care Chapter Highlights Further Reading 10: Cancer Therapy Conventional Anticancer Therapies Inhibit Cell Growth Therapeutic Inhibition of the Cell Cycle Exploiting the Loss of DNA Repair Pathways: Synthetic Lethality On the Horizon: Achieving Synthetic Lethality in TP53-Mutant Cancers Molecularly Targeted Therapy: BCR-ABL and Imatinib Evolution of Therapeutic Resistance Targeting EGFR Mutations Antibody-Mediated Inhibition of Receptor Tyrosine Kinases Inhibiting Hedgehog Signaling Targeting the Pathways that Link KRAS to Cell Growth A Plethora of Rational Targets Dr. Coley´s Remedy of Mixed Toxins: The Birth of Immunotherapy Radiotherapy The Mysterious Abscopal Effect: Radiotherapy as Immunotherapy Immune Checkpoint Blockade Intrinsic Resistance to Immune Checkpoint Blockade Therapy Acquired Resistance to Immune Checkpoint Blockade Therapy Personalized Oncology: Adoptive T-Cell Transfer Cancer Vaccines The Future of Oncology Chapter Highlights Further Reading