Cancer: Principles and Practice of Oncology Primer of the Molecular Biology of Cancer 3rd ed (Eds) Vincent T. DeVita Jr., Theodore S. Lawrence, Steven A. Rosenberg with 71 contributing authors

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
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
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