Cancer Genomics From Bench to Personalized Medicine 1st Edition by Graham Dellaire, Jason Berman, Robert Arceci ISBN 9780123972743 0123972744
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ISBN 10: 0123972744
ISBN 13: 9780123972743
Author: Graham Dellaire, Jason Berman, Robert Arceci
Cancer Genomics addresses how recent technological advances in genomics are shaping how we diagnose and treat cancer. Built on the historical context of cancer genetics over the past 30 years, the book provides a snapshot of the current issues and state-of-the-art technologies used in cancer genomics. Subsequent chapters highlight how these approaches have informed our understanding of hereditary cancer syndromes and the diagnosis, treatment and outcome in a variety of adult and pediatric solid tumors and hematologic malignancies. The dramatic increase in cancer genomics research and ever-increasing availability of genomic testing are not without significant ethical issues, which are addressed in the context of the return of research results and the legal considerations underlying the commercialization of genomic discoveries. Finally, the book concludes with “Future Directions”, examining the next great challenges to face the field of cancer genomics, namely the contribution of non-coding RNAs to disease pathogenesis and the interaction of the human genome with the environment.
- Tools such as sidebars, key concept summaries, a glossary, and acronym and abbreviation definitions make this book highly accessible to researchers from several fields associated with cancer genomics.
- Contributions from thought leaders provide valuable historical perspective to relate the advances in the field to current technologies and literature.
Cancer Genomics From Bench to Personalized Medicine 1st Edition Table of contents:
1 Introduction
1 Historical Perspective and Current Challenges of Cancer Genomics
A Historical Perspective on the Development of Cancer Genomics
Current and Future Challenges
Glossary
Abbreviations
References
2 Genomics Technologies, Concepts and Resources
2 Second-Generation Sequencing for Cancer Genome Analysis
Introduction
Cancer Characterization using Sequencing Approaches
Cancer Is a Genetic Disease
Cancer Properties Are Amenable to Second-Generation Sequence Analysis
Impact of Tumor Heterogeneity on Clinical Diagnosis and Treatments
Advances in Sequencing Technologies
First- and Second-Generation Sequencing Technologies
Progress in Cancer Genomics Research Using Sequencing Approaches
Applications of Second-Generation Sequencing Technologies
Discoveries using Second-Generation Sequencing Technologies
Novel Properties of Cancer
Novel Biomarkers and Therapeutic Targets
Development of Personalized Medicine
Future of Cancer Genome Sequencing
Third-Generation Sequencing Technologies
Clinical Application of Second-Generation Sequencing
Single Cell Genotyping of Bulk Tumors
Conclusion
Glossary
Acronyms and abbreviations
References
3 Cancer Transcriptome Sequencing and Analysis
Introduction
Cancer Transcriptome Sequencing
Experimental Designs
Archival Samples
Handling Tissue Heterogeneity
Cancer Transcriptome Analysis
RNA-Sequencing Data and Analysis Pipelines
Assessing Differential Expression
Quantifying Allele-Specific Expression
Interpreting Cancer Genome-Wide Association Studies
Detecting Fusion Transcripts
Identifying Somatic Single Nucleotide Variants
Identifying Pathogen Presence in Cancer Samples
Future Prospects
Acknowledgments
Glossary
Abbreviations
References
4 The Significance of Transcriptome Sequencing in Personalized Cancer Medicine
Why is RNA important?
From microarray to RNA sequencing
Workflow for RNA-Seq
RNA-Seq data analysis in cancer genome research
Gene Expression Analysis
Non-Coding RNAs
Fusion Genes
Viral Gene Integration
Allelic Imbalance Expression
Pseudogenes
Post-Transcriptional Regulation Analysis
Alternative Splicing
Alternative Cleavage and Polyadenylation
RNA Editing
Computational Approaches for RNA-Seq Analysis
Incorporating transcriptome sequencing analysis to identify genomic driver mutations
Transcriptome sequencing: from bench to bedside
Glossary
Abbreviations
References
5 Tissue Microarrays in Studying Gynecological Cancers
Introduction
Materials and Tissues
Instruments
Arrayers
Microscope
Microtome
Immunostaining Facilities or an Immunostainer
Image Analysis Devices and Software
Tissues
Ethics and Regulatory Issues
Design of Microarrays
Methods and Construction
Selection of Tissues and Cores
Cutting Slides
Antigen Retrieval
Staining
In Situ Hybridization and Fluorescence In Situ Hybridization (ISH and FISH)
Quality Control and Analysis
Slide Conservation and Storage
Staining and Antibody Quality
Scoring and Analysis
Conclusion
Glossary
Abbreviations
References
6 Cancer Pharmacogenomics in Children
Introduction
History of Adverse Drug Reactions in Pediatric Oncology
Adverse Drug Reactions
Pharmacogenomics
Pharmacogenomics of Thiopurine-Induced Toxicity in Children
Pharmacogenomics of Methotrexate-Induced Toxicity in Children
Pharmacogenomics of Cisplatin-Induced Toxicity
Pharmacogenomics of Vincristine-Induced Toxicity
Pharmacogenomics of Anthracycline-Induced Cardiac Toxicity
Need for Collaboration, Active ADR Surveillance and Future Directions
Conclusion
Acknowledgments
Glossary
Abbreviations
References
7 Biomarker Discovery and Development through Genomics
Uses of Biomarkers in Cancer Research and Cancer Care
Biomarker Discovery and Qualification
Important Disclosures during Biomarker Qualification
Assay Validation
The Phases of Assay Analytical Validation
Clinical Validity
Retrospective and Prospective Clinical Validation
Clinical Utility
Guidelines for Assessing Clinical Utility
Incorporation of Biomarkers into Clinical Trial Design
Designing Clinical Trials to Determine Clinical Utility of Biomarkers
Conclusion
Glossary
Abbreviations
References
8 Preclinical Animal Models for Cancer Genomics
History of the Development of Animal Models for Cancer Research
Rodent Animal Models
Other Animal Models
Zebrafish
Dog
Chicken
Invertebrate Models
Transgenic Animal Models
Transgenic Mice – GEMMs and nGEMMs
Transgenic Zebrafish
Xenograft Animal Models
Mouse Xenografts
Chicken Chorioallantoic Membrane Model
Zebrafish Xenografts
Important Considerations in Choosing a Xenograft Approach
Orthotopic vs Heterotopic Xenografts
Xenotransplantation of Cell Lines vs Primary Cancers
Clonal Representation of Primary Human Cancers in Xenografts
Niche/Stromal Interactions and the Humanization of Animal Models
Choosing an Animal Model
Advantages and Drawbacks of Various Animal Models
Xenografts vs Transgenic Models in Mice and Zebrafish
Conclusions
Glossary
Abbreviations
References
9 Bioinformatics for Cancer Genomics
Introduction
Data Types in Cancer Genomics
Whole Genome and Exome Sequence Data
Whole Transcriptome Sequence Data
Proteomic Data
Epigenomic Data
Data Management
Data Analysis
Computational Resources
Analysis Algorithms and Tools
Sequence Alignment and Assembly
Discovery of Point Mutations
Identification of Indels
Structural Variation Detection
Expression Analysis
Analytical Tools
Data Interpretation
Data Integration
Conclusion
Glossary
Abbreviations
References
10 Genomic Resource Projects
Introduction: The Genomic Data Goldmine
Key Large-Scale Cancer Genomics Projects
The Cancer Genome Atlas (TCGA)
International Cancer Genome Consortium (ICGC)
The St Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project (
Other Genomics Projects of Note
Catalogue of Somatic Mutations in Cancer (COSMIC) and dbSNP
Exome Variant Server (EVS)
1000 Genomes Project
Data Sources
Archives
Portals
Processors
Online/Offline Analysis Tools
cBio Cancer Genomics Portal (MSKCC)
PCGP “Explore”
Galaxy
BioMart
My Cancer Genome
Standalone Genome Sequencing Viewers: IGV and More…
Cloud Computing
Synopsis and Prospects (Genomic Resources and the Clinic)
Glossary
Abbreviations
References
3 Hereditary Cancer Syndromes
11 Genetic Basis of Hereditary Cancer Syndromes
Introduction
Retinoblastoma
Wilms tumor
Non-Syndromic Tumors and SusceptibIlity Loci
Neuroblastoma
Sarcomas of Childhood
Cancer Predisposition Syndromes
Cancer Predisposition Syndromes with Malignant-Only Phenotype
Li–Fraumeni Syndrome
Hereditary Paraganglioma Syndromes
DICER1 Syndrome
Multiple Endocrine Neoplasia
Cancer Predisposition Syndromes with Coincident Congenital Anomalies
Beckwith–Wiedemann Syndrome
Gorlin Syndrome
Molecular and Clinical Surveillance for Cancer Predisposition in Children
The Potential Impact of Genome Studies on Hereditary Cancer Syndromes
Glossary
Abbreviations
References
4 Genomics of Adult and Pediatric Cancers
4.1 Adult Solid Tumors
12 Genomics and Molecular Profiling of Lung Cancer
Introduction
Epidemiology
Standard Treatment of Lung Cancer and Prognosis
Surgery
Radiation Therapy
Chemotherapy
Personalized Targeted Therapy
Laser Therapy
Photodynamic Therapy
Cryotherapy
Electrocautery
Somatic Gene Mutations in Lung Cancer
Pathogenesis of Lung Cancer
Molecular Profiling in Lung Cancer
Common Gene Mutations and Clinical Significance
KRAS
EGFR
ALK
BRAF
PIK3CA
HER2
MET
Personalized Targeted Therapy in Lung Cancer
Selection of Targets
EGFR Tyrosine Kinase Inhibitors
Inhibitor against EML4–ALK Fusion Gene
Inhibitors against MET Gene Mutation/Amplification
Other Inhibitors against Gene Mutations
Acquired Resistance and Secondary Mutations
Glossary
References
13 Breast Cancer Genomics
Introduction
Breast Cancer Epidemiology
Breast Anatomy and Development
Hormonal Regulation and Predisposition to Transformation
Breast Cancer Development and Progression: A Step-Wise Phenomenon
Germline and Somatic Aberrations
Epigenetic Deregulation
Breast Cancer Diagnosis and Prognosis: A Historical Overview
Clinical Diagnosis and Prognosis
Histopathological Stage and Tumor Grade
Receptor Statuses (ER, PR and HER2)
Gene Expression Signatures
Breast Cancer Intrinsic Subtypes and PAM 50
ER-Positive Gene Signatures
HER2-Positive Gene Signatures
Triple-Negative Breast Cancer Gene Signatures
Genomic Signatures
Copy Number Aberrations and Integrative Clustering
Intra-Tumoral Heterogeneity and Mutational Signatures
Future of Breast Cancer Prognosis and Treatment
Feasibility of Molecular/Genomic Signatures in Clinical Practice
Non-Invasive Monitoring of Residual and Occult Disease
Need for Standardization and Personalized Medicine
Acknowledgments
Glossary
Abbreviations
References
14 Prostate Cancer Genomics as a Driver of Personalized Medicine
The Need for Genomics in Prostate Cancer Prognosis
Genetic Architecture of Prostate Cancer and Clinical Outcome
Genetics of Prostate Cancer Risk
Genetics of Localized Disease through to Metastases
The Special Case of BRCA1/2-Mutated Tumors
Defining Heterogeneity in Prostate Cancer: Multifocality and Multiclonality
Genome-Wide Sequencing and RNA Expression Studies: Developing Signatures of Clinical Utility
Conclusions: Transferring Genomic Information into Clinical Tests
Acknowledgments
Glossary
Abbreviations
References
15 Genomics of Colorectal Cancer
Introduction
Colorectal Cancer Syndromes
Lynch Syndrome and the Mismatch Repair System
Familial Adenomatous Polyposis
Other Hereditary CRC Syndromes
Genomic Features of Colorectal Cancer and Genome-wide Analyses
Epigenomics
Genome-Wide Association Studies of Colorectal Cancer Susceptibility
Exome/Genome Sequencing and the Identification of Common Somatic Mutations
Structural Variation
Transcriptomics
Non-Coding RNA and Colorectal Cancer
Impact of Common Somatic Mutations on Molecular Pathways in Colorectal Cancer
Molecular Diagnostics and Treatment Guidance
Conclusions and Future Directions
Glossary
Abbreviations
References
16 Thyroid Cancer
Introduction
Papillary Thyroid Carcinoma (PTC)
High Frequency of Oncogenic Chromosomal Rearrangements in PTC
RET/PTC Rearrangements
TRK Rearrangements
ALK Rearrangements
AKAP9/BRAF Rearrangements
BRAF Mutations
RAS Mutations
Follicular Thyroid Carcinoma (FTC)
RAS Oncogenes
PAX8/PPARγ Rearrangements
Mitochondrial Defects
Poorly Differentiated Thyroid Carcinoma (PDTC) and Anaplastic Thyroid Carcinoma (ATC)
Genetic Alterations Shared with DTC
Alterations of the PTEN/PI3K/AKT Pathway
TP53 Mutations
ALK Mutations
β-Catenin Mutations
Expression Profile Studies in Epithelial Thyroid Tumors
Gene Expression
MicroRNA Expression
Medullary Thyroid Carcinoma (MTC)
RET Mutations
RAS Mutations
Conclusions
Glossary
Abbreviations
References
4.2 Age Non-Specific Tumors and Hematopoietic Malignancies
17 Acute Myeloid Leukemia
Introduction
Epidemiology
Etiology
Mutagenic Environmental Exposures
Inherited Predisposition
Genetic and Epigenetic Alterations
Chromosomal Alterations
Karyotypic Alterations
Chimeric Transcription Factors
MLL Gene Rearrangements
Miscellaneous Chromosomal Abnormalities
Sub-Karyotypic Chromosomal Abnormalities
Somatic Mutations and their Contribution to Survival in Childhood AML
Disease-Associated Mutations in Signal Transduction Pathways
FLT3 Mutations
c-KIT Mutations
Nucleophosmin (NPM1) Mutations
CEBPA Mutations
RAS Mutations
Wilms Tumor-1 (WT1) Gene Expression and Mutation
GATA-1 Mutations
Mutations of Genes Affecting Chromatin Structure and Miscellaneous Signaling Pathways
Insights from Genome-Wide Analysis
Epigenetic Changes
Transcriptional Alterations
Integration of Molecular DataSets and Pathway Directed Treatment
Conclusion
Glossary
Abbreviations
References
18 Genomics in Multiple Myeloma: From Conventional Cytogenetics to Novel Whole-Genome Sequencing App
Introduction
Complex Karyotypes in Multiple Myeloma
Balanced Chromosomal Rearrangements in Multiple Myeloma
Translocation t(11;14)
Translocation t(4;14)
MAF Translocations
Chromosomal Imbalances in Multiple Myeloma
Copy Number Variations with Prognostic Significance
Deletion of Chromosome 13
Deletion of Chromosome 17p
Chromosome 1 Abnormalities
Other Common Regions of Copy Number Variations
Chromosome 8 Abnormalities
Chromosome 11 Abnormalities
Chromosome 4, 14, 16 and X Abnormalities
Rare Copy Number Variations
Somatic Mutations
RAS and FGFR3 Mutations
TP53 Mutations
Novel Mutations
NF-κB Mutations
Mutations in RNA Processing Genes
Mutations Involving Genes Important for Protein Homeostasis
Mutations in BRAF
Mutations in Histone-Modifying Genes
Somatic Mutations Stratified by Chromosomal Translocations
Genomic Alterations in MGUS and PCL
Glossary
Abbreviations
References
19 Brain Tumor Genomics: Sequencing to Clinical Utility
Introduction to Brain Tumors
Gliomas
Clinical Presentation and Epidemiology
Classifying Gliomas
Historical Perspective
Current Histopathological Classification and Grading System of Gliomas
Systematic Sequencing of Glioblastoma Genome
Proneural
Neural
Classical
Mesenchymal
Common Mutations in GBM
Epigenetic Alterations in Human Gliomas
DNA Methylation
Histone Modification
Heterogeneity
Current and Future Therapeutic Approaches
Medulloblastoma
Classifying Medulloblastoma
Historical Perspective
Clinical Presentation and Epidemiology
Current Histopathological Classification and Grading System
Systematic Sequencing of Medulloblastoma Genome
Common Mutations in Medulloblastoma
Wnt subgroup
Shh subgroup
Group 3
Group 4
Epigenetic Alterations in Human Medulloblastoma
Treatment
Heterogeneity
Other Brain Tumors
Ependymoma
Pediatric Glioblastoma
Diffuse Intrinsic Pontine Glioma
Conclusion
Glossary
Abbreviations
References
4.3 Pediatric Cancers
20 Genomic Basis of Pediatric Lymphomas
Introduction
Overview of B-Cell Development
Lymphoblastic Lymphoma
B-Lymphoblastic Lymphoma
T-Lymphoblastic Lymphoma
Mature B-Cell Lymphomas
Diffuse Large B-Cell Lymphoma
Burkitt Lymphoma
Anaplastic Large Cell Lymphoma
Conclusions and Future Studies
Glossary
Abbreviations
References
21 Neuroblastoma
Introduction
Germline Predisposition
Familial Neuroblastoma
Predisposition to Sporadic Neuroblastoma
Somatic Changes in Neuroblastoma
Abnormalities of Specific Genes in Neuroblastoma
ALK
ATRX
ARID1A/1B
PTPN11
MYCN Amplification
Chromosomal Abnormalities
17q Gain
11q Loss
1p Loss
Segmental Chromosomal Abnormalities
mRNA Expression and Signatures
Trk Genes
mRNA Expression Signatures
miRNAs
Epigenetics
Host Genomics
Conclusion
Glossary
Abbreviations
References
22 Soft Tissue Sarcomas
Introduction
Genetics
STSs with Simple Karyotypic Defects
STSs with Complex Karyotypic Defects
Histologic Subtypes of STSs
Rhabdomyosarcoma (RMS)
Synovial Sarcoma (SS)
Gastrointestinal Stromal Tumor (GIST)
Congenital Fibrosarcoma (CFS)
Extraosseous Ewing Sarcoma (EES)
Undifferentiated Pleomorphic Sarcoma (UPS)
Leiomyosarcoma (LMS)
Liposarcoma (LPS)
Extraosseous Osteosarcoma
Molecular Diagnosis of STSs
Commonly Deregulated Signaling Pathways in STSs
Insulin-Like Growth Factor 1 Receptor (IGF1R) Pathway
The PI3K/AKT/mammalian Target of Rapamycin (mTOR) Pathway
Notch, Wnt, and Hedgehog (hh) Pathways
Conclusions
Glossary
Abbreviations
References
23 Wilms Tumors
Wilms Tumors
Renal Development
Wilms Tumor Development
WT1
Wnt Signaling
IGF2
Genomics: Bench to Bedside
Overview
DNA Copy Number Analysis
Transcriptomic Analysis
Wilms Tumors with Anaplasia
Next-Generation Sequencing
Wilms Tumor Cancer Stem Cells
Conclusions
Glossary
Abbreviations
References
5 Ethics of Genomics Research
24 Cancer Genomics and Biobanking: Exploring Key Ethical and Legal Issues
Introduction
Vignette Part 1: Olivia’s Leukemia
Part 1. The Ethics of Returning Research Results to Research Participants
The Return of Research Results
Return of a Summary of Results
Return of Individual Results
Is There an Ethical Obligation for Researchers to Offer Individual Research Results?
At What Point Do the Results Reach Adequate Clinical Utility to Offer to Participants?
What Should Researchers Do If the Genomic Results Are Obtained without Prior Specific Consent?
What Should Researchers Do If the Results Are Obtained in a Child? Who Should Be Informed?
What Is the Duration of a Researcher’s Obligation to Share Results?
What Are the Obligations of a Biobank from Which the Specimens Are Obtained?
What Are Researchers’ Obligations to Next of Kin of the Participant?
Vignette Part 2: 10 Years after Olivia’s Donation
Part 2. Biobanks and the Commercialization of Research: Legal and Ethical Issues
Patenting Human Biological Materials and Related Research Findings
The Commercialization of Research and Questions of Benefit-Sharing
Conclusions
Glossary
References
6 Future Directions
25 The Role of MicroRNAs and Ultraconserved Non-Coding RNAs in Cancer
Introduction
miRNAs and Cancer
Deregulated miRNA Expression in Cancer
miRNA Function and Its Involvement in Cancer
miRNAs as Diagnostic Tools
miRNAs as Therapeutic Options
Restoring miRNA Function
Blocking miRNA Function
Challenges
UCGs and Cancer
Deregulated UCG Expression in Cancer
UCGs as Oncogenes or Tumor Suppressors
Conclusion
Glossary
Abbreviations
References
26 The Impact of the Environment on Cancer Genomics
Cancer: A Global Disease
Cancer is a Family of Diseases
Cancer is an Environmental Disease
Narrow and Broad Definitions of Environmental Exposure
The Exposome
Measuring Exposures and Determining Causation
Important Components of the Exposome
Tobacco
Dietary, Physical Activity and Overweight
Alcohol
Occupational Exposures
Radiation
The Social Environment: Impact on the Exposome
Mechanisms of Environmental Carcinogenesis
Genetic and Epigenetic Change
Epigenetics and Environmental Carcinogenesis: Three Examples
Radiation
Arsenic
Folate
Moving Knowledge on Environmental Causes of Cancers Forward: The Role of Omics
Metabolomics
Conclusion
Glossary
Abbreviations
References
Abbreviations
Glossary
Index
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