MOLECULAR PATHOLOGY: THE MOLECULAR BASIS OF HUMAN DISEASE

MOLECULAR PATHOLOGY THE MOLECULAR BASIS OF HUMAN DISEASE
Copyright
Dedication
Preface
List of Contributors
Acknowledgments
1 - Molecular Mechanisms of Cell Death
Introduction
Modes of Cell Death
Structural Features of Necrosis and Apoptosis
Oncotic Necrosis
Apoptosis
Cellular and Molecular Mechanisms Underlying Necrotic Cell Death
Metastable State Preceding Necrotic Cell Death
Mitochondrial Dysfunction and ATP Depletion
Mitochondrial Uncoupling in Necrotic Cell Killing
Mitochondrial Permeability Transition
Inner Membrane Permeability
Mitochondrial Permeability Transition Pore
pH-dependent Ischemia/Reperfusion Injury
Role of the Mitochondrial Permeability Transition in pH-Dependent Reperfusion Injury
Oxidative Stress
Protein Kinase Signaling and the MPT
Other Stress Mechanisms Inducing Necrotic Cell Death
Poly (ADP-Ribose) Polymerase
Plasma Membrane Injury
Pathways to Apoptosis
Roles of Apoptosis in Biology
Plasma Membrane
Mitochondria
Cytochrome c Release
Regulation of the Mitochondrial Pathway to Apoptosis
Antiapoptotic Survival Pathways
Nucleus
Endoplasmic Reticulum
Lysosomes
Shared Pathways to Necrosis and Apoptosis
Programmed Necrosis
Ferroptosis
Pyroptosis
Necroptosis
Concluding Remark
Acknowledgments
References
2 - Acute and Chronic Inflammation Induces Disease Pathogenesis
Introduction
Leukocyte Adhesion, Migration, and Activation
Endothelial Cell Expression of Adhesion Molecules
Chemoattractants
Acute Inflammation and Disease Pathogenesis
Pattern Recognition Receptors and Inflammatory Responses
Toll-Like Receptors
Cytoplasmic Sensors of Pathogens
Pattern Recognition and Pathologic Consequences
Innate Lymphoid Cells
Regulation of Acute Inflammatory Responses
Chronic Inflammation and Acquired Immune Responses
T-Lymphocyte Regulation of Chronic Inflammation
B-Lymphocyte and Antibody Responses
Exacerbation of Chronic Diseases
Tissue Remodeling During Acute and Chronic Inflammatory Disease
Profibrogenic Cytokines and Growth Factors Involved in Fibrotic Tissue Remodeling
TGFβ
TNFα
References
3 - Infection and Host Response
Introduction
Microbes and Hosts—Balance of Power [1]
The Structure of the Immune Response [2–4]
Regulation of Immunity [4]
Pathogen Strategies
Staphylococcus aureus: The Extracellular Battleground
The Innate Immune System: Recognition of Pathogens
Inhibition of Inflammatory Cell Recruitment and Phagocytosis [7–9]
Inhibition of Complement Activation: You Can’t Tag Me! [10]
Inactivation of Antimicrobial Mechanisms [9,11]
Staphylococcal Toxins and Superantigens: Turning the Inflammatory Response on the Host [12]
Mycobacterium tuberculosis and the Macrophage
Mycobacterium and Macrophage: The Pathogen Chooses Its Destiny [13–15]
The Adaptive Response to M. tuberculosis: Containment and the Granuloma [16,17]
Herpes Simplex Virus: Taking Over
Defense Against Viruses: Subversion and Sacrifice [18–20]
Herpes Simplex Virus on the High Wire: A Delicate Balancing Act [22–25]
The African Trypanosome and Antibody Diversity: Dueling Genomes
Generation of Antibody Diversity: Many Ways of Changing [4]
Trypanosoma brucei and Evasion of the Antibody Response: Diversity Responds to Diversity [26,27]
The Trypanosomacidal Serum Factor Story: Host Adaptations to Specific Pathogens and Pathogen Response [28]
HIV: The Immune Guerilla [30,31]
Structure and Transmission of HIV—Small but Deadly [32]
Invasion of Cells by HIV: Into the Lion’s Den [33,34]
Perspectives
References
4 - Neoplasia
Introduction
Cancer Statistics and Epidemiology
Cancer Incidence
General Trends in Cancer Incidence
General Trends in Cancer Mortality in the United States
Global Cancer Incidence and Mortality
Risk Factors for the Development of Cancer
Age, Race, and Gender as Risk Factors for Cancer Development
Family History as a Risk Factor for Cancer Development
Infectious Agents as Risk Factors for Cancer Development
Environmental and Occupational Exposures as Risk Factors for Cancer Development
Lifestyle Exposures as Risk Factors for Cancer Development
Classification of Neoplastic Diseases
Benign Neoplasms
Malignant Neoplasms
Mixed Cell Neoplasms
Confusing Terminology in Cancer Nomenclature
Preneoplastic Lesions
Cancers of Childhood
Hematopoietic Neoplasms
Hereditary Cancers
Characteristics of Benign and Malignant Neoplasms
Cellular Differentiation and Anaplasia
Rate of Growth
Presence of Local Invasion
Metastasis
Clinical Aspects of Neoplasia
Cancer-Associated Pain
Cancer Cachexia
Paraneoplastic Syndromes
Grading and Staging of Cancer
References
5 - Basic Concepts in Human Molecular Genetics
Introduction
Molecular Structure of DNA, DNA Transcription, and Protein Translation
Transcription of DNA
Protein Translation
Molecular Pathology and DNA Repair Mechanisms
Mutation and Genetic Variation
DNA Replication
DNA Repair
Direct Reversal of DNA Damage
Excision Repair of DNA Damage
Mismatch Repair of DNA Damage
Base Excision Repair of DNA Damage
Nucleotide Excision Repair of DNA Damage
DNA Double-Strand Repair of DNA Damage
Modes of Inheritance
Mendelian Inheritance
Autosomal Dominant Inheritance
Autosomal Recessive Inheritance
X-Linked Recessive Inheritance
X-Linked Dominant Inheritance
X-Linked Dominant Male Lethal Inheritance
Y-Linked or Holandric Inheritance
Non-Mendelian Inheritance
Epigenetic Inheritance—Imprinting
Inheritance Through Mitochondrial DNA
Multifactorial Inheritance
Sporadic Inheritance
Differences in Phenotypic Expression Can Complicate Pedigree Analysis
Genetic Penetrance
Sex-Influenced Disorders
Sex-Limited Disorders
Variable Expressivity
Pleiotropy
Anticipation
Other Factors That Complicate Pedigree Analysis
Genetic Mosaicism
Consanguinity
Preferential Marriage Between Affected Individuals
Other Considerations for Pedigree Construction and Interpretation
Central Dogma and Rationale for Genetic Testing
Diagnostic and Predictive Molecular Testing
Benefits of Molecular Testing
Risks Associated With Molecular Testing
Considerations for Selection of a Molecular Test
Allelic Heterogeneity and Choice of Analytical Methodology
Specific Versus Scanning Methods
Specific Mutation Detection
Mutation Scanning Approaches
Interpretation of Molecular Testing Results
Conclusion
References
Further Reading
6 - The Human Genome: Understanding Human Disease in the Post-Genomic Era
Introduction
Structure and Organization of the Human Genome
DNA Carries Genetic Information
General Structure of the Human Genome
Chromosomal Organization of the Human Genome
Subchromosomal Organization of Human DNA
DNA Features
Gene Structure
Overview of the Human Genome Project
The Human Genome Project—Objectives and Strategy
Human Genome Project Findings and Current Status
Impact of the Human Genome Project on the Identification of Disease-Related Genes
Positional Gene Cloning
Functional Gene Cloning
Candidate Gene Approach
Positional Candidate Gene Approach
Sources of Variation in the Human Genome
Types of Genetic Diseases
Genetic Diseases Associated With Gene Inversions
Genetic Diseases Associated With Gene Deletions
Genetic Diseases Associated With Gene Duplications
Genetic Diseases and Cancer
Cystic Fibrosis
Phenylketonuria
Breast Cancer
Nonpolyposis Colorectal Cancer
Perspectives
References
7 - The Human Transcriptome: Implications for Understanding, Diagnosing, and Treating Human Disease
Introduction
Gene Expression Profiling—Early Attempts to Search for Candidate Genes Involved in Normal Physiological Processes and Pathogenes...
Preparation of Target RNA From Biological and Clinical Specimens
Laser Microdissection of Tumor Tissue
Transcriptome Analysis Based on Microarrays—Technical Aspects
Microarray Production
RNA Labeling, Target Amplification, and Hybridization
Array Hybridization: The Classical Two-Color Experiment
Image Analysis and Signal Processing
Transcriptome Analysis Based on RNA Sequencing—Technical Aspects
Sequencing Platforms
Sequencing Workflow
Bioinformatics I—Basic Processing of Microarray and RNA-seq Data
Microarray Data Preprocessing
Microarrays—Normalization
Microarrays—Data Visualization
RNA-seq Data
RNA-seq—Base Calling and Sequencing Quality
RNA-seq—Read Mapping and Transcriptome Reconstruction
RNA-seq—Data Visualization and Inspection of Read Mapping
Bioinformatics II—Exploration and Statistical Evaluation of Transcriptomics Data
Detection of Differential Expression
Classification
Gene Selection
Classification Methods
Cross-validation
Visualization
Clustering
Functional Profiling and Other Enrichment Analyses
Repositories for Transcriptome Data
Trancriptome Analysis—Applications in Basic Research and Translational Medicine
Transcriptomes of Healthy Cells
The Dynamic Transcriptome—Serum Response in Human Cells
Transcriptome Analysis in Cancer Pathogenesis and Diagnosis
Lymphoma Transcriptomes—From Gene Signatures to Simple Gene Predictors
Colorectal Cancer Transcriptomes: Consensus Subtypes Predict Clinical Outcome
Breast Cancer Transcriptomes—Identification of Hidden Subtypes in Breast Cancer Within Apparently Homogenous Cancer Cell Populat...
Prediction of Clinical Outcome of Breast Cancer
Perspectives
References
8 - The Human Epigenome—Implications for the Understanding of Human Disease
Introduction
Epigenetic Regulation of the Genome
The Human Epigenome Project
Genomic Imprinting
Epigenetic Regulation of Imprinted Genes
Imprinted Genes and Human Genetic Diseases
Prader-Willi Syndrome and Angelman Syndrome
Beckwith-Wiedemann Syndrome
Cancer Epigenetics
DNA Hypomethylation in Cancer Cells
Hypermethylation of Tumor Suppressor Genes
Histone Modifications of Cancer Cells
Epigenetic Regulation of Noncoding RNAs in Cancer
Aberrations in Histone-Modifier Enzymes
Human Disorders Associated With Epigenetics
Aberrant Epigenetic Profiles Underlying Immunological, Cardiovascular, Neurological, and Metabolic Disorders
Genetic Aberrations Involving Epigenetic Genes
Syndromes of Disordered Chromatin Remodeling
Alpha-Thalassemia X-Linked Mental Retardation Syndrome
CHARGE Syndrome
Cockayne Syndrome
Schimke Immunoosseous Dysplasia
DNA Methylation-Associated Diseases
Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome
Rett Syndrome
Human Malignancies Associated With Alterations in Histone Modifications
Coffin-Lowry Syndrome
Rubinstein-Taybi Syndrome
Sotos Syndrome
Human Malignancies Associated With Alterations in Noncoding RNAs
DGCR8 Mutations and DiGeorge Syndrome
DICER Mutations in Multinodular 1 Goiter Disease
TARDBP Mutations and Amyotrophic Lateral Sclerosis Type 10 With or Without Frontotemporal Lobar Degeneration
Environment and the Epigenome
References
9 - Clinical Proteomics and Molecular Pathology
Understanding Cancer at the Molecular Level: An Evolving Frontier
Microdissection Technology Brings Molecular Analysis to the Tissue Level
Beyond Functional Genomics to Cancer Proteomics
Protein Microarray Tools to Guide Patient-Tailored Therapy
Molecular Network Analysis of Human Cancer Tissues
Combination Therapies
Protein Biomarker Stability in Tissue: A Critical Unmet Need
Protein Stability Is Unrelated to RNA Transcript Stability
Recognition That the Tissue Is Alive and Reactive Following Procurement
Formalin Fixation May Be Unsuitable for Quantitative Protein Biomarker Analysis in Tissue
Phosphoprotein Stability: The Balance Between Kinases And Phosphatases
Phosphatases Determine Phosphoprotein Stability
Serum Proteomics: An Emerging Landscape for Early-Stage Cancer Detection
Application of Serum Proteomics to Early Diagnosis
The Peptidome: A Recording of the Tissue Microenvironment
Physiologic Roadblocks to Biomarker Discovery
Requirement for New Classes of Diagnostic Technology
Reduction of Bias in the Discovery Phase of Peptide Biomarkers
Methods for Discovering and Validating Candidate Protein Biomarkers
Frontiers of Nanotechnology and Medicine
Future of Cancer Clinical Proteomics
References
Further Reading
10 - Integrative Systems Biology
Introduction
Systems Biology as a Paradigm Shift
Data Generation
Microarrays
Transcriptomics
Genotyping
Other Omic Disciplines
Data Integration
Semantic Web Technologies
Modeling Systems
Implications for Understanding Disease
Redefining Human Diseases
The Transition to Personalized Medicine
Applications of Systems Biology to Medicine
Convergance
Discussion
References
11 - Pathology: The Clinical Description of Human Disease
Introduction
Terms, Definitions, and Concepts
A Brief History of Approaches to Disease
Concepts and Practices Before the Scientific Revolution
The Scientific Revolution
Discovery of the Microscopic World
Critical Developments During the 19th Century
Cellular Pathology, Germ Theory, and Infectious Etiologic Agents
Organic Chemistry
Histotechnology
Developments During the 20th Century
Humoral and Cellular Immunology
Natural Product Chemistry and the Rise of Clinical Laboratories
Natural Product Chemistry: Nucleic Acids
Current Practice of Pathology
The Future of Diagnostic Pathology
Individual Identity
Rapid Cytogenetics
Rapid Nucleic Acid Sequence and RNA Abundance Screening
Computer-Based Prognosis and Prediction
Normal Ranges and Disease Risks by Ethnic Group
Individual Metabolic Differences Relevant to Drug Metabolism
Serum Biomarkers
Conclusion
References
12 - Understanding Molecular Pathogenesis: The Biological Basis of Human Disease and Implications for Improved Treatment of Human Disease
Introduction
Hepatitis C Virus Infection
Identification of the Hepatitis C Virus
Risk Factors for Hepatitis C Virus Infection
Hepatitis C Infection
Testing for Hepatitis C Virus Infection
Clinical Course of Hepatitis C Virus Infection
Treatment of Hepatitis C Infection
Guided Treatment of Hepatitis C Virus
Summary
Acute Myeloid Leukemia
Chromosomal Abnormalities in Acute Myelogenous Leukemia
Consequence of the t(15;17) Translocation In Acute Myelogenous Leukemia
Detection of the t(15;17) Translocation In Acute Myelogenous Leukemia
Summary
Cystic Fibrosis
Cystic Fibrosis Transmembrane Conductance Regulator Gene
Diagnosis of Cystic Fibrosis
Abnormal Function of CFTR in Cystic Fibrosis
Pathophysiology of Cystic Fibrosis
Summary
References
13 - Integration of Molecular and Cellular Pathogenesis: A Bioinformatics Approach
Introduction
Overview of Bioinformatics
Database Resources
Data Analysis
Data Mining Using R
Data Mining Using Weka
Data Mining Using Orange
Interpreting Data Mining Results
The Future of Bioinformatics
References
14 - Molecular Basis of Cardiovascular Disease
Introduction
General Molecular Principles of Cardiovascular Diseases
The Cells of Cardiovascular Organs
Vascular Endothelial Cells
Vascular Smooth Muscle Cells
Valve Endocardial Cells
Valve Interstitial Cells
Leukocytes
Vascular and Cardiac Progenitor/Stem Cells
Cardiac Stem Cells
Atherosclerosis
Stage I: Plaque Initiation and Formation
Stage II: Adaptation Stage
Stage III: Clinical Stage
Ischemic Heart Disease
Aneurysms
Vasculitis
Valvular Heart Disease
Mitral Valve Prolapse
Calcific Aortic Stenosis
Cardiomyopathies
Cardiomyocyte Structure and Function
Molecular Genetics and Pathogenesis of Hypertrophic Cardiomyopathy
Molecular Genetics and Pathogenesis of Dilated Cardiomyopathy
Cytoskeletal Defects
Sarcomeric Defects
Molecular Genetics and Pathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy
Molecular Genetics and Pathogenesis of Noncompaction Cardiomyopathy
Channelopathies
Lymphatic Circulation
References
15 - Molecular Basis of Hemostatic and Thrombotic Diseases
Introduction and Overview of Coagulation
Disorders of Soluble Clotting Factors
Fibrinogen Abnormalities
Prothrombin (Factor II) Deficiency
Factor V Deficiency
Factor VII Deficiency
Hemophilia A and Hemophilia B (Classic Hemophilia and Christmas Disease)
Factor X Deficiency
Factor XI Disorders
Deficiencies of Factor XII, Prekallikrein, and High-Molecular-Weight Kininogen
Factor XIII Deficiency
Multiple Clotting Factor Deficiencies
Von Willebrand Disease
Disorders of Fibrinolysis
Disorders of Platelet Number or Function
Disorders of Platelet Production
The MYH9-Associated Disorders
Defects in Transcription Factors
Defects in Platelet Production
Disorders of Platelet Function
Defects in Platelet Adhesion
Defects in Platelet Aggregation
Disorders of Platelet Secretion: The Storage Pool Diseases
Defects in Alpha Granules
Defects in Dense Granules
The Scott Syndrome
Disorders of Platelet Destruction
Antibody-Mediated Platelet Destruction
Thrombotic Microangiopathies
Heparin-Induced Thrombocytopenia
The Thrombophilias
The Protein C/S Pathway and Thrombosis
Antithrombin Deficiency
References
16 - Molecular Basis of Lymphoid and Myeloid Diseases
Introduction
Development of the Blood and Lymphoid Organs
Hematopoietic Stem Cells
Bone Marrow Niche
Spleen
Thymus
Lymph Nodes
Hematopoietic Differentiation and the Role of Transcription Factors
Hematopoietic Differentiation and the Role of Signal Transduction
Myeloid Disorders
Anemia
Neutropenia
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Overlap Diseases and Myeloproliferative Neoplasms
Chronic Myelomonocytic Leukemia
Juvenile Myelomonocytic Leukemia
Atypical Chronic myeloid Leukemia and Myelodysplastic/Myeloproliferative Disease, Unclassifiable
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Polycythemia Vera
Essential Thrombocythemia
Primary Myelofibrosis
Chronic Eosinophilic Leukemia/Hypereosinophilic Syndrome
Systemic Mastocytosis
Stem Cell Leukemia-Lymphoma Syndrome
Acute Myeloid Leukemia
AML With t(8;21) (q22;q22)
AML With inv(16)(p13q22) or t(16;16)(p13q22)
Acute Promyelocytic Leukemia With t(15;17)(q22q12)
AML With 11q23 (MLL) Abnormalities
Cytogenetically Normal AML
Therapy-Related AML and MDS
Role of miRNAs in AML
Lymphocyte Disorders
Lymphopenia
Lymphocytosis
Neoplastic Problems of Lymphocytes
Acute Lymphoblast Leukemia/Lymphoma
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Follicular Lymphoma
Diffuse Large B-cell Lymphoma
Burkitt Lymphoma
Multiple Myeloma
Hodgkin Lymphoma
Outlook for the Treatment of Leukemia
References
Further Reading
17 - Molecular Basis of Diseases of Immunity
Introduction
The Normal Immune System
Cells
B-Cells
T-Cells
Natural Killer Cells
Dendritic Cells
Macrophages
Granulocytes
Molecules
Complement
Antibodies
T-Cell Receptors
Major Histocompatibility Complex
Cytokines
Chemokines
Toll-Like Receptors
Immune Responses
Innate Immune Responses
Adaptive Immune Responses
Major Syndromes
Hypersensitivity Reactions
Type I or Immediate Hypersensitivity
Type II or Antibody-Mediated Hypersensitivity
Type III or Immune Complex Reaction
Type IV or Delayed-Type Hypersensitivity
Immunologic Deficiencies
Primary Immunodeficiencies
X-Linked Agammaglobulinemia (Bruton Disease)
Hyper-IgM Syndrome
Complement Deficiency
Severe Combined Immunodeficiency
Common Variable Immunodeficiency
Chronic Granulomatous Disease
X-Linked Proliferative Disease (Duncan Syndrome)
Hyper-IgE Syndrome
Inherited Susceptibility to Herpes Encephalitis
Inherited Susceptibility to Mycobacterial Infections
Inherited Susceptibility to Mucocutaneous Candidiasis
Acquired Immunodeficiencies
Acquired Immune Deficiency Syndrome
Cytokine Autoantibodies
Autoimmune Diseases
Systemic Lupus Erythematosus
Type 1 Diabetes Mellitus
Multiple Sclerosis
Celiac Disease
The Hygiene Hypothesis
References
18 - Molecular Basis of Pulmonary Disease
Introduction
Neoplastic Lung and Pleural Diseases
Common Molecular Genetic Changes in Lung Cancers
Adenocarcinoma and Its Precursors
Clinical and Pathologic Features
Molecular Pathogenesis
Squamous Cell Carcinoma and Its Precursors
Clinical and Pathologic Features
Molecular Pathogenesis
Large Cell Carcinoma
Neuroendocrine Neoplasms and Their Precursors
Clinical and Pathologic Features
Molecular Pathogenesis
Mesenchymal Neoplasms
Pleural Malignant Mesothelioma
Clinical and Pathologic Features
Molecular Pathogenesis
Nonneoplastic Lung Disease
Chronic Obstructive Lung Disease—Emphysema/Chronic Bronchitis
Clinical and Pathologic Features
Molecular Pathogenesis
Bronchiectasis
Clinical and Pathologic Features
Molecular Pathogenesis
Interstitial Lung Diseases
Idiopathic Interstitial Pneumonias—Usual Interstitial Pneumonia
Clinical and Pathology Features
Molecular Pathogenesis
Surfactant Dysfunction Diseases
Pulmonary Alveolar Proteinosis
Clinical and Pathologic Features
Molecular Pathogenesis
Hereditary Disorders of Surfactant Dysfunction
Clinical and Pathologic Features
Molecular Pathogenesis
Pulmonary Vascular Diseases
Pulmonary Hypertension
Clinical and Pathologic Features
Molecular Pathogenesis
References
19 - Molecular Basis of Diseases of the Gastrointestinal Tract
Introduction
Gastric Cancer
Nonhereditary Gastric Cancer
Risk Factors
Stepwise Progression of H. pylori Gastritis to Gastric Carcinoma: Histologic Changes of the Gastric Mucosa
Molecular Mechanisms Underlying Gastric Epithelial Neoplasia Associated With H. pylori Infection
Mechanisms and Spectrum of Epigenetic Changes, Mutagenesis, and Gene Expression Changes of the Gastric Epithelium Induced by H. ...
Mutational, Epigenetic, Gene Expression, and MicroRNA Patterns of Gastric Intestinal Metaplasia, Dysplasia/Adenoma, and Cancer
The Cancer Genome Atlas Research Network—Molecular Characterization of Gastric Adenocarcinomas
Genomic Alterations in EBV-Associated Gastric Adenocarcinomas
MSI Cancers
GS Cancers
CIN Cancers
Familial Gastric Cancer
Genetic and Molecular Basis of Familial and Hereditary Gastric Cancer
Hereditary Diffuse Gastric Cancer: Genetic Basis
Hereditary Diffuse Gastric Cancer: Molecular Mechanisms, Clinical and Pathologic Features
Natural History and Pathologic Features
Molecular Mechanisms and Pathologic Correlates
Hereditary Diffuse Gastric Cancer: Genetic Testing and Clinical Management
Colorectal Cancer
Sporadic Colon Cancer
Molecular Mechanisms of Neoplastic Progression in Inflammatory Bowel Disease
Natural History of Neoplasia in Inflammatory Bowel Disease
Molecular Mechanisms of Colorectal Cancer Development and Progression in IBD-Associated Colitis
IBD-Associated Neoplasia: Diagnosis and Clinical Management
Hereditary Nonpolyposis Colorectal Cancer
Hereditary Nonpolyposis Colorectal Cancer: Genetic and Molecular Basis
Hereditary Nonpolyposis Colorectal Cancer: Natural History, Clinical and Pathologic Features, and Molecular Mechanisms
Hereditary Nonpolyposis Colorectal Cancer: Molecular Diagnosis, Clinical Management, and Genetic Counseling
Familial Adenomatous Polyposis and Variants
Familial Adenomatous Polyposis: Genetic Basis
Familial Adenomatous Polyposis: Natural History and Clinical, Molecular, and Pathologic Features
Familial Adenomatous Polyposis and Related Syndromes: Molecular Diagnosis, Clinical Management, and Genetic Counseling
References
20 - Molecular Basis of Liver Disease
Molecular Basis of Liver Development
Molecular Basis of Metabolic Zonation in the Liver
Molecular Basis of Liver Regeneration
Liver Stem Cells in Liver Health and Disease
Molecular Basis of Hepatocyte Death
Fas-Activation-Induced Liver Injury
TNF-α-Induced Liver Injury
Molecular Basis of Nonalcoholic Fatty Liver Disease
Diet, Insulin Resistance, and the Adipose–Tissue–Liver Axis
Role of Fructose in Nonalcoholic Fatty Liver Disease
Insulin Resistance
Intestinal Permeability, Gut Dysbiosis, and the Gut–Liver Axis
Intestinal Permeability and the Gut–Liver Axis
Gut-Derived Hormones
Intestinal Dysbiosis
Common Pathways of Hepatocyte Lipotoxicity, Injury, Repair and Cell Death
Lipotoxicity and Factors Modifying Lipotoxicity
Inflammation and Signaling Pathways of Inflammation
Oxidative Stress and Lipid Peroxidation
Mitochondrial Dysfunction
Endoplasmic Reticulum Stress and the Unfolded Protein Response
Autophagy
Role of the Hepatic Wound Healing Response and Associated Pathways
Hepatic Progenitor Cells
Extracellular Vesicles
MicroRNA
Nuclear Receptors
Telomere Shortening
Cell Death
Genetic Factors
Molecular Basis of Alcoholic Liver Disease
Alcohol Metabolism and Generation of Oxidative Stress
Common Pathways of Hepatocyte Injury in Alcoholic Liver Disease
Apoptosis, Necrosis, and Necroapoptosis
Hypoxia
Innate and Adaptive Immune Responses
Gut–Liver Axis in Alcoholic Liver Disease
Genetic Factors Predisposing to Alcoholic Liver Disease
Molecular Basis of Hepatic Fibrosis and Cirrhosis
Molecular Basis of Hepatic Tumors
Benign Liver Tumors
Hemangioma
Focal Nodular Hyperplasia
Hepatocellular Adenoma
Malignant Liver Tumors
Hepatoblastoma
Hepatocellular Cancer
Fibrolamellar Hepatocellular Cancer
References
21 - Molecular Basis of Diseases of the Exocrine Pancreas
Introduction
Acute Pancreatitis
Early Events in Acute Pancreatitis and the Role of Protease Activation
The Mechanism of Zymogen Activation
The Degradation of Active Trypsin
The Role of Autophagy in Acute Pancreatitis
Calcium Signaling
Inflammation: Cause and Consequence of Acinar Cell Damage
Chronic and Hereditary Pancreatitis
Mutations Within the PRSS1 Gene
Mutations Within the PRSS2 Gene
Mutations in the Chymotrypsin C Gene
Mutations in Serine Protease Inhibitor Kazal Type 1
Mutations in Genes Independent of Trypsin Processing
CFTR Mutations—A New Cause of Chronic Pancreatitis
Summary
References
22 - Molecular Basis of Diseases of the Endocrine System
Introduction
The Pituitary Gland
Combined Pituitary Hormone Deficiency
Homeobox Expressed in Embryonic Stem Cells 1
LIM Homeobox Protein 3 and 4
Prophet of Pit-1
POU Domain, Class 1, Transcription Factor 1
Zinc Finger Protein Gli2
GHRH-GH-IGF1 Axis
Growth Hormone–Releasing Hormone Receptor
Growth Hormone
Growth Hormone Receptor
Insulin-Like Growth Factor 1
Growth Hormone Hypersecretion
The Thyroid Gland
Hypothyroidism
Central Congenital Hypothyroidism
Thyroid Dyshormonogenesis
Resistance to Thyroid Hormone
Thyroid Hormone Receptor
Thyroid Hormone Cell Transporter
Familial Nonautoimmune Hyperthyroidism
The Parathyroid Gland
Calcium Homeostasis
Hypoparathyroidism
Familial Isolated Hypoparathyroidism
Familial Hypoparathyroidism as Part of a Complex Congenital Defect
Hyperparathyroidism
Familial Isolated Hyperparathyroidism
Multiple Endocrine Neoplasia Type 1
Multiple Endocrine Neoplasia Type 2
Hyperparathyroidism-Jaw Tumor Syndrome
Calcium-Sensing Receptor and Related Disorders
Disorders due to Loss-of-Function Mutations of Calcium-Sensing Receptor
Disorders due to Gain-of-Function Mutation of the Calcium-Sensing Receptor
The Adrenal Gland
Congenital Primary Adrenal Insufficiency
Adrenal Hypoplasia Congenita
Congenital Adrenal Hyperplasia
Adrenocorticotropic Hormone Resistance Syndromes
Secondary Adrenal Insufficiency
Generalized Glucocorticoid Resistance/Insensitivity
Hypercortisolism (Cushing Syndrome)
Puberty
Delayed Puberty
Hypogonadotropic Hypogonadism
Hypergonadotropic Hypogonadism
Precocious Puberty
Gonadotropin-Dependent Precocious Puberty
Gonadotropin-Independent Precocious Puberty
Acknowledgments
References
23 - Molecular Basis of Gynecologic Diseases
Introduction
Benign and Malignant Tumors of the Female Reproductive Tract
Cervix
Human Papillomaviruses Associated With Cervical Lesions and Cancer
Human Papillomavirus Infection and Life Cycle
Detection of Human Papillomavirus–Associated Lesions
Diagnosis and Treatment
Prevention and Vaccines
Molecular Mechanisms of High-Risk Human Papillomavirus–Mediated Cellular Transformation
Biological and Biochemical Activities of High-Risk HPV E7 Oncoproteins
Biological and Biochemical Activities of High-Risk HPV E6 Oncoproteins
Contributions of Human Papillomavirus Oncoproteins to Induction of Genomic Instability
Concluding Remarks
Uterine Corpus
Epithelial Cancers
Ovary and Fallopian Tube
Polycystic Ovary Syndrome
Benign Ovarian Cysts
Borderline Tumors
Malignant Tumors
Vagina and Vulva
Disorders Related to Pregnancy
Gestational Trophoblastic Diseases
Epigenetic Changes in Trophoblastic Diseases
Immunology and Trophoblastic Diseases
Oncogenes and Tumor Suppressor Gene Alterations in Trophoblastic Diseases
Diagnosis of Molar Pregnancies
Detection of Trophoblastic Diseases
Molecular Basis of Preeclampsia
References
24 - Molecular Basis of Kidney Disease
Introduction
Clinical Manifestations
Diagnosis of Renal Disease
Serum Measurements of Renal Function
Urinalysis
Renal Biopsy
Biomarkers for Diagnosis and Prognosis
Specific Glomerular and Tubular Diseases
Diabetic Nephropathy
Clinical and Pathologic Features
Molecular Pathogenesis
Membranous Nephropathy
Clinical and Pathologic Features
Molecular Pathogenesis
Focal Segmental Glomerulosclerosis
Clinical and Pathologic Features
Molecular Pathogenesis
IgA Nephropathy
Clinical and Pathologic Features
Pathologic Mechanisms
Membranoproliferative Glomerulonephritis
Clinical and Pathologic Features
Molecular Pathogenesis
Polycystic Kidney Disease
Acute Tubular Necrosis
Clinical and Pathological Features
Molecular Pathogenesis
Acute Interstitial Nephritis
Tubulointerstitial Fibrosis
Tubulointerstitial Fibrosis as a Final Common Pathway of CKD
Molecular Mechanisms
Priming: Inflammation Generates a Profibrotic Environment
Activation: Recruitment of Matrix-Producing Cells
Execution: Assembly and Activation of the Fibrogenic Matrisome
Progression: Damage Above and Beyond Scar Formation
Conclusions
References
25 - Molecular Pathogenesis of Prostate Cancer
Introduction
Incidence and Etiology of Prostate Cancer
Genetic Contributions to Prostate Cancer Risk
Somatic Alterations in Gene Expression
MYC
NKX3.1
PTEN
Androgen Receptor
TMPRSS2-ETS Gene Fusions
p27kip1
Telomeres
MicroRNAs
Epigenetics
GSTP1
APC
Advances in Mouse Models of Prostate Cancer
Conditional Loss of Tumor Suppressor Gene Expression in the Prostate
Loss of RB
Overexpression of Oncogenes in the Prostate
Overexpression of Mutated Androgen Receptor
Hepsin
Conclusion
References
26 - Molecular Biology of Breast Cancer
Introduction
Histopathological Classification
Histopathological Features of Breast Cancer
Histological Type
Lobular Neoplasia
Ductal Carcinoma In Situ
Invasive Ductal Carcinoma
Vascular Invasion
Perineural Invasion
Histological Grading
Biomarkers
Estrogen Receptor
Resistance to Endocrine Therapy
Testing for Estrogen Receptor
Progesterone Receptor
The HER2 Receptor
Identifying the HER2 Receptor
Targeting HER2: Trastuzumab
The Androgen Receptor
Proliferative and Stromal Biomarkers
Ki67
Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor
Tumor-Infiltrating Lymphocytes
Multifocal Breast Cancer
Gene Expression Profiling
Microarray Technology
Molecular Classification of Breast Cancer
Gene Expression Signatures to Refine Prognostication
Signatures of Immune Response
Massively Parallel Sequencing
Polymerase Chain Reaction
Hybrid Capture
The Molecular Landscape of Breast Cancer and Novel Classification
Molecular Characterization of Specific Populations
Triple-Negative Breast Cancer
Invasive Lobular Breast Carcinoma
Male Breast Cancer
Emerging Targets
ESR1 Alterations
ERBB2 Mutations
Conclusions
References
27 - Molecular Basis of Skin Disease
Introduction
Skin Diseases and Their Impact
Molecular Basis of Healthy Skin
Skin Development and Maintenance Provide New Insight Into the Molecular Mechanisms of Disease
Molecular Pathology of Mendelian Genetic Skin Disorders
Molecular Pathology of Common Inflammatory Skin Diseases
Skin Proteins as Targets for Inherited and Acquired Disorders
Molecular Pathology of Skin Cancer
Molecular Diagnosis of Skin Disease
New Molecular Mechanisms and Novel Therapies
References
28 - Molecular Basis of Bone Diseases
Introduction
Molecular Basis of Bone Modeling and Remodeling
Interplay Between the Immune System and Bone: Osteoimmunology and RANK-RANKL-OPG System
Molecular Basis of Bone Disease Associated With Bone Matrix
Osteogenesis Imperfecta
Autosomal Dominant Osteogenesis Imperfecta
Recessive Osteogenesis Imperfecta
Osteoporosis
Estrogen Regulation
Genetic Regulation
Regulation of Gene Expression by MicroRNA
Regulation of Signaling Pathways
Regulation of Local and Systemic Growth Factors
Inflammatory Modulators
Molecular Basis of Bone Disease Associated With Bone Resorption
Osteopetrosis
Paget Disease of Bone
Molecular Basis of Metabolic Bone Disease
Vitamin D Metabolism
Parathyroid Hormone
Renal Osteodystrophy
Molecular Basis of Bone Infection and Inflammation
Prosthetic Joint Infection
Autoinflammatory Bone Disorders
Sporadic CNO
Majeed Syndrome
Inflammosomopathies
Cherubism
Hypophosphatasia
Primary Hypertrophic Osteoarthropathy
Molecular Basis of Bone Cancer
Benign Tumors
Osteochondroma
Giant Cell Tumors of Bone
Osteoblastoma
Osteoma and Osteoid Osteoma
Aneurysmal Bone Cyst
Fibrous Dysplasia
Enchondroma
Bone Cancer
Osteosarcoma
WNT Signaling Pathway in Bone Cancer
Glycogen Synthase Activity-3β (GSK3β)/NFkB Signaling in Bone Cancer
Cyclin-Dependent Kinase Signaling in Bone Cancer
p53 Signaling in Bone Cancer
Phophatidylinositol-3-Kinase (PI3K)/AKT Pathway Signaling in Bone Cancer
GLI2 Transcription Factor and Hedgehog Pathway Signaling in Bone Cancer
SPHK1/ASK1/JNK/CHK1 Signaling in Bone Cancer
Pigmented Epithelium-Derived Factor Signaling in Bone Cancer
miRNA in OSA
OSA Metastasis
Ewing Sarcoma
Chordoma
Molecular Basis of Bone Metastasis
Osteolytic and Osteoblastic Bone Metastasis
Premetastatic Niche and Disseminated Cancer Cells
Genes Involved in Bone Metastasis
miRNA and Bone Metastasis
References
29 - Molecular Basis of Diseases of the Nervous System
Anatomy of the Central Nervous System
Microscopic Anatomy
Gray Matter
White Matter
Cerebrospinal Fluid and the Ventricular System
Gross Anatomy
Summary
Neurodevelopmental Disorders
Gastrulation and Neurulation: Neural Tube Defects
Organizing the Central Nervous System: Signaling Centers and Regional Patterning
Neural Tube Closure and Wnt-PCP Signaling
Human Neural Tube Defects
Rostrocaudal and Dorsoventral Patterning of the Neural Tube: Holoprosencephaly
Holoprosencephaly
Signaling Centers and Transcription Factor Gradients in the Cerebral Cortex: Thanatophoric Dysplasia
Thanatophoric Dysplasia
Compartmentalization of Embryonic Neurogenesis
Proliferation, Progenitors, and Apoptosis: Micrencephaly and Megalencephaly
Neuroepithelial Cells and Radial Glia
Intermediate Neuronal Progenitors
Adult Neurogenesis
Gliogenesis
Apoptosis
Micrencephaly
Megalencephaly
Neuronal Migration and Differentiation: Lissencephaly
Postmitotic Events and Integration Into Neural Circuits
Neuronal Differentiation
Neuronal Migration
Lissencephaly, Periventricular Heterotopia, and Polymicrogyria
Axon Growth and Guidance: Agenesis of the Corpus Callosum
Agenesis of the Corpus Callosum
Synaptogenesis, Refinement, and Plasticity: Autism and Schizophrenia
Summary
Neurological Injury: Stroke, Neurodegeneration, and Toxicants
Basic Mechanisms of Injury
Excitotoxicity
Mitochondrial Dysfunction
Free Radical Stress
Lipid Peroxidation
Carbonyl Stress
Innate Immune Activation
Catechol Metabolites
Vascular Disease and Injury
Ischemia
Hemorrhage
Degenerative Diseases
Etiology
Pathogenesis of Neurodegeneration
Neurotoxicants
Neuropathological Changes Caused by Neurotoxicants
Biochemical Mechanisms of Selected Neurotoxicants
Domoic Acid
MPTP
Axonotoxicants
Neoplasia
Diffuse Gliomas
Diffuse Astrocytoma-Glioblastoma Sequence
Oligodendroglioma
Circumscribed Gliomas
Medulloblastoma
Other Neuroepithelial Tumors
Metastasis and Lymphoma
Disorders of Myelin
Leukodystrophies
Demyelination
Idiopathic Demyelinating Disease
Animal Model of Demyelination
Acquired Metabolic Demyelination
Infectious Demyelination
References
30 - Molecular Diagnosis of Human Disease
Introduction
Regulatory Agencies and CLIA
Quality Assurance, Quality Control, and External Proficiency Testing
Method Validation
Clinical Utility
Molecular Laboratory Subspecialties
Heritable Disorders
Fragile X Syndrome
Validation of Molecular Sizing of FMR1
PCR and Capillary Electrophoresis
Statistical Analysis
Postanalytical Considerations
Benefit/Risk Assessment (Clinical Utility)
Infectious Diseases
Enteroviral Disease
Validation of LightCycler-Based, Reverse Transcription-PCR Assay for Enterovirus
Preanalytical Considerations
Postanalytical Considerations
Benefit/Risk Assessment (Clinical Utility)
Hepatitis C Viral Genotype
Validation of Hepatitis C Virus Genotyping
Statistical Analysis
Preanalytical Considerations
Postanalytical Considerations
Benefit/Risk Assessment (Clinical Utility)
Oncology
B Cell and T Cell Clonality
Validation of B Cell and T Cell Clonality Assays
Preanalytical Considerations
Postanalytical Considerations
Benefit/Risk Assessment (Clinical Utility)
Genomics
Solid Tumor–Targeted Mutation Panel via Next Generation Sequencing
Preanalytical Considerations
Postanalytical Considerations
Future Directions
Liquid Biopsies
Gene Expression Profiling
Pharmacogenomics
References
Further Reading
31 - Molecular Assessment of Human Diseases in the Clinical Laboratory
Introduction
Molecular Pathology Techniques
PCR-Based Methods
The Polymerase Chain Reaction
Reverse Transcription-PCR
Real-Time PCR (qPCR)
Multiplex PCR
Digital PCR
Array-Based Sequence Captures
Microarray Probes
Types of Microarray
Printed Arrays
In Situ–Synthesized Oligonucleotide Microarrays
High-Density Bead Arrays
Suspension Bead Arrays
Clinical Uses of Microarray Technologies
Mass Spectrometry
MALDI-TOF MS
Nucleic Acid Detection
Protein Detection
Nucleic Acid Sequencing
Sanger Sequencing
Next-Generation Sequencing or Massively Parallel Sequencing
Library Preparation
Template Amplification
Sequencing Methods
Data Analysis
Methylation Detection Techniques
PCR-Based DNA Methylation Assays
Methylation-Specific PCR
MethyLight Assay
Methylation-Specific Sequencing Methods
Sanger Sequencing
Pyrosequencing
Mass Spectrometry
Clinical Applications
Oncology
Genomics
Somatic Mutation Profile
Copy Number Variation
Epigenomics
Transcriptomics
Gene Expression Profiling
Gene Fusion
miRNA
Infectious Diseases
Qualitative Analysis
Pathogen Detection and Identification
Genotypic Characterization
Quantitative Analysis
Drug Resistance
Genetic Disorders
Single Gene Disorders—Cystic Fibrosis
Trinucleotide Repeat Disorders—Fragile X Syndrome
Polygenic/Multifactorial Disorders—Developmental Disabilities or Congenital Anomalies
Emerging Technologies
Liquid Biopsies for Molecular Diagnosis
Oncology
Cancer Diagnosis and Screening
Cancer Molecular Profiling
Prognosis, Residual Disease, and Risk Relapse
Monitoring Disease Burden and Treatment Monitoring
Obstetrics
References
32 - Pharmacogenomics and Personalized Medicine in the Treatment of Human Diseases
Introduction
Historical Perspective
Genotyping Technologies
PGx and Drug Metabolism
CYP2D6
CYP2C9
Drug–Drug Interactions
PGx and Drug Triansporters
ABCB1
PGx and Drug Targets
OPRM1
DRD1/2
PGx Applied to Oncology
UGT1A1
TPMT
Targeted Therapies in Oncology
Estrogen Receptor
HER2
EGFR
FLT3
BCR-ABL
Challenges Encountered
Conclusion
References
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
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T
U
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W
X
Y
Z