Cancer: Principles and Practice of Oncology Primer of the Molecular Biology of Cancer

Contributors
PART I: Principles of Molecular Oncology
	1. The Cancer Genome
	Yardena Samuels, Alberto Bardelli, Yochai Wolf, and Carlos López-Otin
	Introduction
	Cancer Genes and Their Mutations
	Identification of Cancer Genes
	Cancer Gene Discovery by Sequencing Candidate Gene Families
	Mutational Analysis of Exomes Using Sanger Sequencing
	Next-Generation Sequencing and Cancer Genome Analysis
	Whole-Genome Analysis Utilizing Second-Generation Sequencing
	Whole-Exome Analysis Utilizing Second-Generation Sequencing
	Somatic Alteration Classes Detected by Cancer Genome Analysis
	Pathway-Oriented Models of Cancer Genome Analysis
	Passenger and Driver Mutations
	Networks of Cancer Genome Projects
	The Genomic Landscape of Cancers
	Single-Cell Genomics
	Integrative Analysis of Cancer Genomics
	Immunogenomics
	The Cancer Genome and the New Taxonomy of Tumors
	Liquid Biopsies as a Diagnosis Tool
	Clinical Applications of Liquid Biopsies
	Cancer Genomics and Drug Resistance
	Perspectives of Cancer Genome Analysis
	Acknowledgments
	2. Molecular Methods in Cancer
	Larissa V. Furtado, Jay L. Hess, and Bryan L. Betz
	Applications of Molecular Diagnostics in Oncology
	Biomarker Genetics
	Use of Biomarkers in Diagnosis
	Use of Biomarkers in Prognosis
	Use of Biomarkers in Predicting Response to Therapy
	Use of Biomarkers in Therapeutic Disease Monitoring
	Use of Biomarkers in Risk Assessment and Cancer Prevention
	The Clinical Molecular Diagnostics Laboratory: Rules and Regulations
	Specimen Requirements for Molecular Diagnostics
	Molecular Diagnostics Testing Process
	Targeted Mutation Analysis Methods
	Polymerase Chain Reaction
	Real-time Polymerase Chain Reaction
	Reverse-Transcription Polymerase Chain Reaction
	Allele-Specific Polymerase Chain Reaction
	Fragment Analysis
	Sanger Sequencing
	Pyrosequencing
	Methylation Analysis
	Microsatellite Instability Analysis/Assessment of Mismatch Repair Deficiency
	Fluorescence In Situ Hybridization
	Whole-Genome Analysis Methods
	Next-Generation Sequencing
	Genomic Microarrays
	Expression Panels
	Immunohistochemistry for Tumor Biomarkers
	PD-L1
	ALK and ROS1
	BRAFV600E
	Cell-Free DNA Technologies
	3. Hallmarks of Cancer: An Organizing Principle for Cancer Medicine
	Douglas Hanahan and Robert A. Weinberg
	Introduction
	Hallmark Capabilities, In Essence
	Sustaining Proliferative Signaling
	Somatic Mutations Activate Additional Downstream Pathways
	Disruptions of Negative-Feedback Mechanisms that Attenuate Proliferative Signaling
	Excessive Proliferative Signaling Can Trigger Cell Senescence
	Evading Growth Suppressors
	Mechanisms of Contact Inhibition and Its Evasion
	Corruption of the Transforming Growth Factor β Pathway Promotes Malignancy
	Resisting Cell Death
	Autophagy Mediates Both Tumor Cell Survival and Death
	Necrosis Has Proinflammatory and Tumor-Promoting Potential
	Enabling Replicative Immortality
	Reassessing Replicative Senescence
	Delayed Activation of Telomerase May Both Limit and Foster Neoplastic Progression
	Inducing Angiogenesis
	Gradations of the Angiogenic Switch
	Endogenous Angiogenesis Inhibitors Present Natural Barriers to Tumor Angiogenesis
	Pericytes Are Important Components of the Tumor Neovasculature
	A Variety of Bone Marrow–Derived Cells Contribute to Tumor Angiogenesis
	Activating Invasion and Metastasis
	The Epithelial-to-Mesenchymal Transition Program Broadly Regulates Invasion and Metastasis
	Heterotypic Contributions of Stromal Cells to Invasion and Metastasis
	Plasticity in the Invasive Growth Program
	Distinct Forms of Invasion May Underlie Different Cancer Types
	The Daunting Complexity of Metastatic Colonization
	Reprogramming Energy Metabolism
	Evading Immune Destruction
	Two Ubiquitous Characteristics Facilitate the Acquisition of Hallmark Capabilities
	An Enabling Characteristic: Genome Instability and Mutation
	An Enabling Characteristic: Tumor-Promoting Inflammation
	The Constituent Cell Types of the Tumor Microenvironment
	Cancer-Associated Fibroblasts
	Endothelial Cells
	Pericytes
	Immune Inflammatory Cells
	Stem and Progenitor Cells of the Tumor Stroma
	Heterotypic Signaling Orchestrates the Cells of the Tumor Microenvironment
	Coevolution of the Tumor Microenvironment During Carcinogenesis
	Cancer Cells, Cancer Stem Cells, and Intratumoral Heterogeneity
	Therapeutic Targeting of the Hallmarks of Cancer
	Conclusion and a Vision for the Future
	Acknowledgment
	4. Oncogenic Viruses
	Christopher B. Buck, Lee Ratner, and Giovanna Tosato
	Principles of Tumor Virology
	Papillomaviruses
	History
	Tissue Tropism and Gene Functions
	Human Papillomavirus Vaccines
	Oropharyngeal Cancer
	Nonmelanoma Skin Cancer
	Bladder Cancer
	Polyomaviruses
	History
	BK Polyomavirus
	Merkel Cell Polyomavirus
	Other Human Polyomaviruses
	Epstein-Barr Virus
	History
	Epstein-Barr Virus Life Cycle
	Lymphomas
	Carcinomas
	Prevention and Treatment
	Kaposi Sarcoma Herpesvirus
	History and Epidemiology
	Kaposi Sarcoma–Associated Herpesvirus in Kaposi Sarcoma
	Lymphoproliferative Disorders
	Animal and Human Retroviruses
	Human T-Cell Leukemia Virus Epidemiology
	Human T-Cell Leukemia Virus Molecular Biology
	Clinical Characteristics and Treatment of Human T-lymphotropic Virus 1–Associated Malignancies
	Hepatitis Viruses
	Hepatitis B Virus
	Hepatitis C Virus
	Hepatitis Virus Pathogenesis
	Clinical Characteristics and Treatment of Hepatitis Virus–Associated Malignancies
	Conclusion
	5. DNA Repair in Normal and Cancer Cells
	Meredith A. Morgan and Theodore S. Lawrence
	Introduction
	Radiation-Induced DNA Damage
	Cellular Responses to Radiation-Induced DNA Damage
	Cell Cycle Checkpoint Pathways
	DNA Repair
	Metabolism
	Innate Immune Response
	Chromosome Aberrations Result from Faulty DNA Double-Strand Break Repair
	Membrane Signaling
	The Effect of Radiation on Cell Survival
	In Vivo Survival Determination of Normal Tissue Response to Radiation
	In Vivo Determination of Tumor Response to Radiation
	Factors That Affect Radiation Response
	The Fundamental Principles of Radiobiology
	Dose-Rate Effects
	Relative Biologic Effectiveness
	Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy
	Cell Cycle
	Tumor Oxygenation
	Immune Response
	Genetic Signatures
	Drugs That Affect Radiation Sensitivity
	Antimetabolites
	Platinums and Temozolomide
	Taxanes
	Molecularly Targeted Agents
	Immunotherapy
	Radiation Protection
	6. Microbiome and Cancer
	Giorgio Trinchieri
	Introduction
	Cancer as a Disease of the Metaorganism
	Bacteria as Cause of Cancer
	Helicobacter pylori and Stomach Cancer
	Colorectal Cancer
	Tumors in Tissues Not Directly Colonized by the Microbiota
	The Microbiota Modulates Cancer-Predisposing Conditions and Comorbidity
	Bacteria as Cancer Drugs
	Microbiota and Drug Metabolism
	Microbiota and Chemotherapy
	Microbiota and Immunotherapy
	Immune Checkpoint Blockers: Anti-CTLA-4
	Immune Checkpoint Blockers: Anti-PD-1/PD-L1
	Looking Forward
	7. Precision Medicine in Oncology
	James H. Doroshow
	Introduction
	Approach to Precision Medicine in Oncology
	Next-Generation DNA Sequencing for Precision Oncology
	Broadening the Spectrum of Molecular Characterization
	Preclinical Models to Inform Precision Oncology
	Role of Molecular Pharmacodynamics and Diagnostics in Precision Oncology
	Human Biospecimens for Molecular Characterization
	Molecular Pharmacodynamics in Precision Oncology
	Predictive Diagnostic Assays
	Precision Oncology Clinical Trials and Trial Designs
	Imaging and Precision Oncology
	Precision Prevention
	Future Prospects
	8. Cancer Immunotherapy
	Jeffrey Weber and Iulia Giuroiu
	Introduction
	Interferon-α
	Interleukin-2
	Talimogene Laherparepvec
	Granulocyte Macrophage Colony-Stimulating Factor
	Tumor-Infiltrating Lymphocytes
	Checkpoint Inhibitors—Cytotoxic T-Lymphocyte Antigen 4 and Programmed Cell Death Protein 1
	Cytotoxic T-Lymphocyte Antigen 4 Blockade
	Programmed Cell Death Protein 1 and Programmed Cell Death Protein Ligand 1 Blockade
	Melanoma
	Non–small-cell Lung Cancer
	Mismatch-Repair Deficient or Microsatellite Instability-High Cancers
	Renal Cell Carcinoma
	Hodgkin Lymphoma
	Head and Neck Squamous Cell Carcinoma
	Urothelial Carcinoma
	Merkel Cell Carcinoma
	Hepatocellular Carcinoma
	Gastric Cancer
	Cervical Cancer
	Primary Mediastinal Large B-Cell Lymphoma
	Dosing
	Vaccines
	Sipuleucel-T
	Conclusion
	9. Immunotherapy Agents
	Jeffrey A. Sosman and Douglas B. Johnson
	Introduction
	Human Tumor Antigens
	Mutanome-Associated Neoantigens
	Tumor Vaccines
	Personalized Neoantigen Vaccination
	Immune Checkpoint Inhibitors
	Other Immune Checkpoint Inhibitors in Development
	Anti-TIGIT
	TIM-3
	LAG-3
	KIR
	CD73
	VISTA
	B7-H3
	Immune Checkpoint Activators
	4-1BB (CD137)
	GITR
	ICOS
	CD40
	CD27-CD70
	OX40
	Oncolytic Viruses
	Talimogene Laherparepvec
	Other Oncolytic Viruses
	Factors to Activate Immune Effector Cells
	Cytokines
	IL-2 Variant Molecules
	Signaling Modulation
	STAT3 Inhibition
	PI3Kδ Inhibitors
	PI3Kγ Inhibitors
	Chemokine Inhibitors
	CXCR2 Inhibitors
	CCR2 Inhibitors
	CXCR4 Inhibitors
	CCR4 Antibodies
	CCR5 Inhibitors
	Soluble Factors
	IDO Inhibition
	Arginase Inhibitor
	TGF-β Kinase Inhibitors
	Adenosine A2α Receptor Axis
	Adenosine Receptor Inhibitors
	Innate Immune Modulation
	Pathogen-Associated Molecular Patterns, Damage-Associated Molecular Patterns, and Pattern Recognition Receptors
	Toll-Like Receptor Modulators
	STING Agonists
	Anti-CD47 Monoclonal Antibodies
	Colony-Stimulating Factor 1 Receptor Inhibition
	Bifunctional Fusion Proteins
	Immunocytokines
	Adoptive Cell Therapy
	Chimeric Antigen Receptor T-Cell Therapy
	10. Monoclonal Antibodies
	Hossein Borghaei, Matthew K. Robinson, Gregory P. Adams, and Louis M. Weiner
	Introduction
	Immunoglobulin Structure
	Structural and Functional Domains
	Modified Antibody-Based Molecules
	Factors Regulating Antibody-Based Tumor Targeting
	Antibody Size
	Tumor Antigens
	Half-Life/Clearance Rate
	Glycosylation
	Unconjugated Antibodies
	Cell-Mediated Cytotoxicity
	Complement-Dependent Cytotoxicity
	Altering Signal Transduction
	Immunoconjugates
	Antibody–Drug Conjugates
	Radioimmunoconjugates
	Antibodies Approved for Use in Solid Tumors
	Trastuzumab
	Pertuzumab
	Cetuximab
	Panitumumab
	Necitumumab
	Bevacizumab
	Ado-Trastuzumab Emtansine
	Ramucirumab
	Denosumab
	Antibodies Used in Hematologic Malignancies
	Rituximab
	ofatumumab
	Alemtuzumab
	Brentuximab Vedotin
	Inotuzumab Ozogamicin
	Obinutuzumab
	Blinatumomab
	Daratumumab
	Elotuzumab
	Dinutuximab
	Olaratumab
	Conclusion
	11. Cancer Susceptibility Syndromes
	Alice Hawley Berger and Pier Paolo Pandolfi
	Introduction
	Principles of Cancer Susceptibility
	The “Two-Hit” Paradigm
	What Is the Function of a Tumor Suppressor?
	Haploinsufficiency and Compound Haploinsufficiency
	Genetic Testing
	Cancer Susceptibility Syndromes
	Retinoblastoma
	Incidence
	Genetic Basis
	Molecular Mechanism
	Mouse Models
	Clinical Features and Therapeutic Intervention
	Most Prevalent Syndromes
	Lynch Syndrome
	Hereditary Breast and Ovarian Cancer
	Neurofibromatosis Type 1
	Familial Adenomatous Polyposis
	Other Syndromes, by Function
	Genomic Integrity and Apoptosis
	Regulation of Protein Translation
	Proliferation
	Angiogenesis
	Principles of Cancer Chemoprevention
	Emerging Knowledge and New Lessons
	Germline Mutations in Sporadic Cancer
	Weak Modifiers
	Epigenetic Factors
	Role of Noncoding RNAs
	The Regulatory Genome
	High-Throughput Methods for Understanding Cancer Variants
	Conclusion
	12. Pharmacogenomics
	Christine M. Walko and Howard L. McLeod
	Introduction
	Pharmacogenomics of Tumor Response
	Pathway-Directed Anticancer Therapy
	Genetic-Guided Therapy: Practical Issues in Somatic Analysis
	Pharmacogenomics of Chemotherapy Drug Toxicity
	Thiopurine Methyltransferase
	Dihydropyrimidine Dehydrogenase
	Conclusions and Future Directions
	13. Genetic Counseling
	Danielle C. Bonadies, Meagan B. Farmer, and Ellen T. Matloff
	Introduction
	Who is a Candidate for Cancer Genetic Counseling?
	Components of the Cancer Genetic Counseling Session
	Precounseling Information
	Family History
	Dysmorphology Screening
	Risk Assessment
	Genetic Testing
	Options for Surveillance, Risk Reduction, and Tailored Treatment
	Follow-up
	Issues in Cancer Genetic Counseling
	Genetic Test Selection and Approaches
	Management of the Patient with a Pathogenic Variant in a Moderate-Risk or Lesser Known Gene
	Genetic Testing in Children
	Reproductive Issues
	Potential Germline Implications of Tumor Genomic Profiling
	Changes in Delivery Models
	Direct-to-Consumer Genetic Testing
	Psychosocial Issues
	Confidentiality
	Insurance and Discrimination Issues
	Future Directions
	Whole-Genome Sequencing and Whole-Exome Sequencing
	General Population Testing
	CRISPR
	Conclusion
PART II: Molecular Biology of Individual Cancers
	14. The Molecular Biology of Head and Neck Cancers
	Thomas E. Carey, Mark E. Prince, and J. Chad Brenner
	Incidence, Risk Factors, and Etiology
	Oral Tongue Cancer in Young Patients
	High-Risk Hpv in Oropharyngeal Cancer
	Molecular Mechanisms in Hnscc
	The Cancer Genome Atlas Project
	Inhibition of Hnscc Immune Escape
	Cancer Stem Cells
	15. The Molecular Biology of Lung Cancer
	Jill E. Larsen and John D. Minna
	Introduction
	Genomics: Tools for Identification, Prediction, and Prognosis
	Somatic Landscape of Lung Cancer
	Characterization of Aberrant Pathways
	Transcriptome Profiling
	Proteomic Approaches
	Lessons Learned and Future Directions
	Functional Genomics in Lung Cancer
	Genome-wide RNA-Based and shRNA-Based Screening
	CRISPR-Cas9 Gene Editing
	Preclinical Model Systems for Studying Lung Cancer
	Genetic and Epigenetic Alterations in Lung Cancer
	EGFR/HER2/MET Signaling
	EGFR
	ERBB2 (HER2)
	MET
	RAS/RAF/MAPK Pathway
	RAS
	RAF
	MEK (MAP2K1 or MEK1)
	MYC
	Pl3K/AKT/mTOR Pathway
	STK11 (LKB1)
	Insulin Growth Factor Pathway
	Fibroblast Growth Factor Pathway
	The p53 Pathway
	The p16INK4a-RB Pathway
	Fusion Proteins
	ALK
	ROS1
	RET
	NTRK
	BRAF
	EGFR
	Epigenetic Changes in Lung Carcinogenesis
	Methylation and Chromatin Remodeling
	Noncoding RNAs
	NFIB, a Metastasis-Inducing Transcription Factor
	KDM Lysine Demethylases (JumonjiC) as an Epigenomic Drug Resistance Mechanism
	Metastasis and the Tumor Microenvironment
	Epithelial-to-Mesenchymal Transition
	Angiogenesis
	Immune Checkpoint Inhibition
	Exosomes as a Source of Information on Tumor Molecular Alterations
	Lung Cancers Stem Cells
	Telomerase-Mediated Cellular Immortality in Lung Cancer
	Clinical Translation of Molecular Data
	Current Translation of Rationale-based Targeted Therapy
	Potential for Future Clinical Translation
	16. Molecular Biology of the Esophagus and Stomach
	Anil K. Rustgi
	Introduction
	Molecular Biology of Esophageal Cancer
	Epidermal Growth Factor Receptor
	Cyclin D1 and p16INK4a
	TP53 Tumor Suppressor Genes
	Telomerase Activation
	Tumor Invasion and Metastasis
	Models of Esophageal Squamous Cell Cancer and Esophageal Adenocarcinoma
	Functional Genomics
	Molecular Biology of Gastric Cancer
	Inherited Susceptibility
	Role of Helicobacter pylori Infection and Other Host–Environmental Factors
	Molecular Genetic Alterations
	Models of Gastric Cancer
	17. The Molecular Biology of Pancreas Cancer
	Scott E. Kern and Ralph H. Hruban
	Introduction
	Common Genetic Changes in Pancreatic Ductal Adenocarcinoma
	Less-Prevalent Genetic Changes in Pancreatic Ductal Adenocarcinoma
	Other Neoplastic Lesions
	18. Molecular Biology of Liver Cancer
	Jens U. Marquardt and Snorri S. Thorgeirsson
	Introduction
	Genetic Alterations in Liver Cancer
	Epigenetic Alterations in Liver Cancer
	Mutational Landscape of Genetic Alterations—The Next Generation
	The Microenvironment of Liver Cancer
	Classification and Prognostic Prediction of Hepatocellular Carcinoma
	Molecular Basis of Cholangiocarcinoma
	Conclusion and Perspective
	19. Molecular Biology of Colorectal Cancer
	Ramesh A. Shivdasani
	Introduction
	Multistep Models of Colorectal Cancer and Genetic Instability
	Mutational and Epigenetic Landscapes in Colorectal Cancer
	Insights from Mouse Intestinal Crypts and Human Colorectal Cancers Lead to a Coherent Model for Colorectal Cancer Initiation and Progression
	WNT Signaling
	Other Growth Factor Pathways
	Inherited Syndromes of Increased Cancer Risk Highlight Early Events and Critical Pathways in Colorectal Tumorigenesis
	Familial Adenomatous Polyposis and the Central Importance of WNT Signaling
	Hereditary Nonpolyposis Colorectal Cancer and the Role of DNA Mismatch Repair
	Other Inherited Syndromes with Elevated Colorectal Cancer Risk
	Familial Juvenile Polyposis
	Insights from Mendelian Syndromes, Genome-Wide Association Studies, and the Microbiome
	Oncogene and Tumor Suppressor Gene Mutations in Colorectal Cancer Progression
	The KRAS, BRAF, and PIK3CA Oncogenes
	MYC, CDK8, and Control of Cell Growth and Metabolism
	TP53 and Other Tumor Suppressors
	Prognostic and Predictive Value of Tumor Genotypes and Molecular Properties
	20. Molecular Biology of Kidney Cancer
	W. Marston Linehan and Laura S. Schmidt
	Introduction
	Clear Cell Renal Cell Carcinoma
	von Hippel-Lindau Disease
	Genetics of von Hippel-Lindau Disease: VHL Gene
	Gene Mutated in Renal Cancer Families with Chromosome 3p Translocations
	Sporadic Clear Cell Kidney Cancer: VHL Gene Mutation
	Function of the von Hippel-Lindau Protein
	Additional Genes Mutated in Clear Cell Kidney Cancer
	Papillary Renal Cell Carcinoma
	Hereditary Papillary Renal Carcinoma: Type 1 Papillary
	Genetics of Hereditary Papillary Renal Carcinoma: MET Protooncogene
	Hereditary Papillary Renal Carcinoma: Functional Consequences of MET Mutations
	Sporadic Type 1 Papillary Renal Cell Carcinoma
	Xp11.2 Translocation Renal Cell Cancer
	Hereditary Leiomyomatosis and Renal Cell Carcinoma: Type 2 Papillary
	Hereditary Leiomyomatosis and Renal Cell Carcinoma: Fumarate Hydratase Gene
	Functional Consequences of Fumarate Hydratase Mutations
	Sporadic Type 2 Papillary Renal Cell Carcinoma
	Chromophobe Renal Cell Carcinoma
	Birt-Hogg-Dubé Syndrome
	Birt-Hogg-Dubé Syndrome: FLCN Gene
	Function of the Birt-Hogg-Dubé Protein: Folliculin
	Sporadic Chromophobe Renal Cell Carcinoma
	Additional Types of Renal Cell Carcinoma
	Tuberous Sclerosis Complex
	Succinate Dehydrogenase–Associated Renal Cancer
	Conclusion
	21. Molecular Biology of Bladder Cancer
	Carolyn D. Hurst and Margaret A. Knowles
	Introduction
	Mutational Landscape
	Mutation Rates, Mutational Signatures, and Mutational Processes
	FGFR3, PIK3CA, and RAS Genes
	Telomerase Reverse Transcriptase Promoter
	TP53, RB1, and CDKN2A
	Genes Involved in Chromatin Modification and Architecture
	STAG2
	Alterations in DNA Repair Pathways
	Structural Alterations to the Genome
	Heterogeneity and Clonal Evolution
	Molecular Subtypes
	DNA-Based Subtypes
	Transcriptome-Based Subtypes
	Therapeutic Opportunities and Future Outlook
	22. The Molecular Biology of Prostate Cancer
	Charles Dai and Nima Sharifi
	Introduction
	The Genomic Landscape of Prostate Cancer
	The Molecular Subtypes of Primary Prostate Cancer
	ETS Family Gene Fusions
	Speckle-Type POZ Protein Mutations
	Forkhead Box A1 Mutations
	Serine Peptidase Inhibitor, Kazal Type 1 Overexpression
	Isocitrate Dehydrogenase 1 Mutations
	The Clonal Evolution of Lethal Metastatic Prostate Cancer
	Genetic Basis of Prostate Cancer Heritability
	Androgen Signaling in Prostate Cancer
	androgen Receptor Structure and Function
	androgen Receptor Action
	Intratumoral androgen Biosynthesis
	Glucocorticoid Signaling in Treatment Resistance
	Other Signaling Pathways in Prostate Cancer
	Phosphatidylinositol 3-Kinase/AKT/Mammalian Target of Rapamycin Pathway
	Other Signaling Pathways in Prostate Cancer
	Cell Cycle Aberrations
	Neuroendocrine Prostate Cancer
	Areas of Ongoing Research and Emerging Therapeutic Approaches
	DNA Repair Pathway
	Epigenetic Alterations
	Conclusion
	23. Molecular Biology of Gynecologic Cancers
	Tanja Pejovic, Adam J. Krieg, and Kunle Odunsi
	Introduction
	Ovarian Cancer
	Origins of Epithelial Ovarian Cancer
	Molecular Pathways to Ovarian Cancer
	Inherited Syndromes of Ovarian Cancers
	Targeting Homologous Recombination Defects in Gynecologic Cancer
	Ovarian Cancer Microenvironment, Metastases, and Angiogenesis
	Ovarian Cancer Microenvironment
	Angiogenesis and Tumor Hypoxia
	Influences of the Microenvironment on Tumor Metastasis
	Epigenetics
	Role of Specific Immune Responses and Immunotherapy
	Immune Inhibitory Network and Immune Checkpoint Inhibitors in Ovarian Cancer
	Immunotherapy Clinical Trials in Ovarian Cancer
	Adoptive Cellular Transfer Therapy
	Endometrial Cancer
	Type I Cancers
	Type II Endometrial Cancer
	Microsatellite Instability
	PTEN
	KRAS Mutations
	β-Catenin
	Cervix, Vaginal, and Vulvar Cancers
	Role of Human Papillomavirus
	Immune Evasion by Human Papillomavirus
	Human Papillomavirus Vaccines
	Adoptive T-Cell Therapy
	24. Molecular Biology of Breast Cancer
	Ana T. Nunes, Tara Berman, and Lyndsay Harris
	Introduction
	Genetics of Breast Cancer
	Hereditary Breast Cancer
	High-Penetrance, Low-Frequency Genes
	Moderate-Penetrance, Low-Frequency Genes
	Low-Penetrance, High-Frequency Genes and Loci
	Microsatellite Instability in Breast Cancer
	Somatic Alterations in Breast Cancer
	Copy Number Alterations in Breast Cancer
	Transcriptional Profiles of Breast Cancer—Molecular Subtypes
	Luminal Subtypes
	HER2-Enriched Subtype
	Triple-Negative Subtypes
	Mutational Profiles in Breast Cancer by Molecular Subtype
	Transcriptional Profiles of Breast Cancer—Prognosis and Benefit of Therapy
	70-Gene Assay (Mammaprint)
	21-Gene Recurrence Score (Oncotype DX)
	Prediction Analysis of Microarray-50 (PAM50, PAM50 Risk of Recurrence Score, or Prosigna)
	12-Gene Risk Score (Endopredict)
	Two-Gene Ratio (Breast Cancer Index)
	Epigenetics of Breast Cancer
	Protein/Pathway Alterations
	Estrogen Receptor Pathway
	Growth Factor Receptor Pathways
	Human Epidermal Growth Factor Receptor 2
	RAS and Phosphatidylinositol 3-Kinase Signaling Pathways
	Cyclin-Dependent Kinases
	25. Molecular Biology of Endocrine Tumors
	Zeyad T. Sahli, Brittany A. Avin, and Martha A. Zeiger
	Endocrine Syndromes
	Multiple Endocrine Neoplasia Type 1
	Clinical Features
	Molecular Genetics of MEN1
	Multiple Endocrine Neoplasia Type 2
	Clinical Features of MEN2A
	Clinical Features of MEN2B
	Molecular Genetics of MEN2
	Multiple Endocrine Neoplasia Type 4
	Carney Complex
	Clinical Features
	Molecular Genetics of Carney Complex
	Adrenal Gland
	Cortisol-Producing Adenomas
	Aldosterone-Producing Adenomas
	Pheochromocytoma
	Adrenocortical Carcinoma
	Parathyroid Gland
	Hyperparathyroidism–Jaw Tumor Syndrome
	Familial Hypocalciuric Hypercalcemia
	Neonatal Severe Hyperparathyroidism
	Autosomal Dominant Hypoparathyroidism
	Familial Isolated Hyperparathyroidism
	Pituitary Gland
	Familial Isolated Pituitary Adenoma
	X-linked Acrogigantism
	McCune-Albright Syndrome
	Paraganglioma, Pheochromocytoma, and Pituitary Adenoma Association
	Dicer1 Syndrome
	Thyroid Gland
	Follicular Adenomas
	Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features
	Papillary Thyroid Cancer
	Follicular Thyroid Cancer
	Hürthle Cell Carcinoma
	Medullary Thyroid Cancer
	Anaplastic Thyroid Cancer
	Werner Syndrome
	Acknowledgments
	26. Molecular Biology of Sarcomas
	Samuel Singer and Cristina R. Antonescu
	Introduction
	Soft Tissue Sarcomas
	Translocation-Associated Soft Tissue Sarcomas
	Myxoid/Round Cell Liposarcoma
	Ewing Sarcoma
	Desmoplastic Small Round Cell Tumor
	Synovial Sarcoma
	Alveolar Rhabdomyosarcoma
	Alveolar Soft Part Sarcoma
	Dermatofibrosarcoma Protuberans
	Extraskeletal Myxoid Chondrosarcoma
	Solitary Fibrous Tumor and Hemangiopericytoma
	Soft Tissue Sarcomas of Simple Karyotype Associated With Mutations
	Desmoid Fibromatosis
	Complex Soft Tissue Sarcoma Types
	Well-Differentiated and Dedifferentiated Liposarcoma
	Pleomorphic Liposarcoma
	Myxofibrosarcoma and Undifferentiated Pleomorphic Sarcoma (Malignant Fibrous Histiocytoma)
	Myxofibrosarcoma
	Undifferentiated Pleomorphic Sarcoma (Malignant Fibrous Histiocytoma)
	Leiomyosarcoma
	Malignant Peripheral Nerve Sheath Tumor
	Angiosarcoma
	Bone and Cartilaginous Tumors
	Cartilaginous Tumors
	Enchondroma
	Osteochondroma
	Chondrosarcoma
	Osteosarcoma
	Future Directions: Next-Generation Sequencing and Functional Screens
	27. Molecular Biology of Cutaneous Melanoma
	Michael A. Davies
	Introduction
	The Cancer Genome Atlas Effort in Cutaneous Melanoma
	The Ras-Raf-Mapk Pathway
	RAF Kinases
	RAS Family GTPases
	NF1
	Additional Oncogenic Pathways
	Cell Cycle Regulators
	The p53 Pathway
	The Phosphatidylinositol 3-Kinase Pathway
	Receptor Tyrosine Kinases
	RAC1
	Telomerase
	Triple Wild-Type Melanomas
	Melanin Synthesis Pathway
	MITF
	The MC1R Pathway
	Summary and Future Directions
	28. Molecular Biology of Central Nervous System Tumors
	Mark W. Youngblood, Jennifer Moliterno Günel, and Murat Günel
	Introduction
	Pediatric Brain Tumors
	Medulloblastoma
	Low-Grade Glioma
	High-Grade Glioma
	Ependymal Tumors
	Adult Brain Tumors
	Low-Grade Glioma
	High-Grade Glioma
	Meningioma
	Summary
	Acknowledgments
	29. Molecular Biology of Lymphoma
	Nicolò Compagno, Laura Pasqualucci, and Riccardo Dalla-Favera
	Introduction
	The Cell of Origin of Lymphoma
	B-Cell Development and the Dynamics of the Germinal Center Reaction
	T-Cell Development
	General Mechanisms of Genetic Alterations in Lymphoma
	Chromosomal Translocations
	Aberrant Somatic Hypermutation
	Copy Number Gains and Amplifications
	Activating Point Mutations
	Inactivating Mutations and Deletions
	Infectious Agents
	Molecular Pathogenesis of B-Cell Non-Hodgkin Lymphoma
	Mantle Cell Lymphoma
	Cell of Origin
	Genetic Lesions
	Burkitt Lymphoma
	Cell of Origin
	Genetic Lesions
	Follicular Lymphoma
	Cell of Origin
	Genetic Lesions
	Diffuse Large B-Cell Lymphoma
	Cell of Origin
	Genetic Lesions
	Primary Mediastinal B-Cell Lymphoma
	Cell of Origin
	Genetic Lesions
	Marginal Zone Lymphoma
	Cell of Origin
	Genetic Lesions
	Chronic Lymphocytic Leukemia
	Cell of Origin
	Genetic Lesions
	Molecular Pathogenesis of T-Cell Non-Hodgkin Lymphoma
	Adult T-Cell Leukemia/Lymphoma (HTLV-1 Positive)
	Cell of Origin
	Genetic Lesions
	Angioimmunoblastic T-Cell Lymphoma
	Cell of Origin
	Genetic Lesions
	Peripheral T-Cell Lymphoma Not Otherwise Specified
	Genetic Lesions
	Cutaneous T-Cell Lymphoma
	Anaplastic Large-Cell Lymphoma
	Cell of Origin
	Genetic Lesions
	Hepatosplenic T-Cell Lymphoma
	Molecular Pathogenesis of Hodgkin Lymphoma
	Cell of Origin
	Genetic Lesions
	30. Molecular Biology of Acute Leukemias
	Glen D. Raffel and Jan Cerny
	Introduction
	Leukemic Stem Cell
	Elucidation of Genetic Events in Acute Leukemia
	Mutations Affecting Transcription Factors
	Core-Binding Factor
	Retinoic Acid Receptor Alpha Gene
	HOX Family Members
	C/EBPα
	GATA Factors
	Mutations that Result in Overexpression of c-MYC
	Mutation of Lymphoid Development Factors in Acute Lymphoid Leukemia
	Chromosomal Translocations Involving the T-cell Receptor
	RBM15/MKL1
	Mutations of Epigenetic Modifiers
	KMT2A (aka MLL) Translocations
	MOZ and TIF2
	TET2
	DNMT3A
	ASXL1
	EZH2
	Mutations Affecting Signaling
	Oncogenic RAS Mutations
	Activating Mutations in Tyrosine Kinases and Associated Receptors
	BCR/ABL1
	FLT3
	KIT
	MPL
	JAK/STAT Pathway
	CRLF2
	Kinases in Ph-Negative Acute Lymphoid Leukemia
	Mutations in Tumor Suppressor Genes
	WT1
	TP53
	Activating Mutations of Notch
	Mutations Altering Localization of Npm1
	Mutations in Cohesin Complex Genes
	Mutations in Splicing Machinery
	Mutational Complementation Groups in Acute Leukemias
	Conclusion
	31. Molecular Biology of Chronic Leukemias
	Christopher A. Eide, James S. Blachly, and Anupriya Agarwal
	Introduction
	Chronic Myeloid Leukemia
	Pathogenesis
	Molecular Anatomy of the BCR-ABL1 Junction
	Functional Domains of BCR-ABL1 and Kinase Activation
	Signal Transduction
	Phosphatidylinositol-3 Kinase
	Rat Sarcoma/Mitogen-Activated Protein Kinase Pathways
	Janus Kinase/Signal Transducer and Activator of Transcription Pathway
	DNA Repair
	Chronic Myeloid Leukemia Stem Cells
	Progression to Blastic Phase
	Chronic Myeloid Leukemia Bone Marrow Microenvironment
	Conclusions
	Chronic Lymphocytic Leukemia
	Origin of Chronic Lymphocytic Leukemia
	Chromosomal Abnormalities in the Pathogenesis of Chronic Lymphocytic Leukemia
	Recurrent Mutations in Chronic Lymphocytic Leukemia
	Progression of Chronic Lymphocytic Leukemia: The Role of Genomic Instability and Clonal Evolution
	Chronic Lymphocytic Leukemia and Proliferation
	Chronic Lymphocytic Leukemia and Disrupted Apoptosis
	B-cell Receptor Signaling in Chronic Lymphocytic Leukemia
	Conclusion
	Acknowledgments
Index
Copyright
Title Page
Dedication
Contents
Chapter 1: ‘I’m thinking’ – Oh, but are you?
Chapter 2: Renegade perception
Chapter 3: The Pushbacker sting
Chapter 4: ‘Covid’: The calculated catastrophe
Chapter 5: There is no ‘virus’
Chapter 6: Sequence of deceit
Chapter 7: War on your mind
Chapter 8: ‘Reframing’ insanity
Chapter 9: We must have it? So what is it?
Chapter 10: Human 2.0
Chapter 11: Who controls the Cult?
Chapter 12: Escaping Wetiko
Postscript
Appendix: Cowan-Kaufman-Morell Statement on Virus Isolation
Bibliography
Index