Chapter
2 Cancer Genome Methylation: Biology, Biomarker and Therapeutic Opportunities
DNA methylation mechanisms
DNA methylation and cancer
DNA methylation as cancer biomarker
Epigenetic therapeutics in cancer
Conclusion and perspectives
3 MicroRNA Biomarkers for Early Detection of Cancer
MicroRNA discovery and non-coding RNA types
MicroRNA biogenesis and mechanism of action
MicroRNAs act as oncogenes and tumor suppressor genes
MicroRNAs in cancer detection and prediction
MicroRNAs as risk indicators
MicroRNAs for detecting cancer and improving standard diagnostic tools
Extracellular MicroRNAs as biomarkers of early detection
MicroRNAs in combination with other genomic and clinical indicators
New development of miRNA research
MicroRNA reproducibility and validation for cancer detection
4 Inflammation and Cancer
Introduction: inflammation
Infection-induced inflammation
Inflammation in sterile tissue injury
Tumor-promoting inflammatory cells
Tumor-promoting inflammatory cytokines and chemokines
Molecular pathways and networks that regulate tumor promoting inflammation
Tumor-associated antigens and inflammation
Disease-associated antigens in immunosurveillance of cancer and inflammation
Preventing tumor-promoting inflammation by eliciting DAA specific immunity: example from inflammatory bowel disease (IBD) promoting colitis associated colon cancer (CACC)
5 Exosomes: A Valuable Biomedical Tool in Biomarker Discovery and Development
Biogenesis and characterization of exosomes
Diagnostic potential of exosomal RNA
Diagnostic potential of exosomal proteins
Role in immune regulation and tumor development
Exosomes from tumor cells
Recent developments in utilization of exosomes as biomarkers for cancer
Challenges in exosome utilization
Challenges in exosome-based diagnostics
6 Epithelial-to-Mesenchymal Transition (EMT): Clinical Implications
Biology of epithelial-to-mesenchymal transition (EMT)
EMT: effects on cells and tissues
Induction of EMT: contribution of the tumor microenvironment
Stromal cells in tumors and their role in EMT induction
Carcinoma-associated fibroblasts and endothelial cells
Epithelial-to-mesenchymal transition regulators
Mesenchymal-to-epithelial transition (MET)
EMT: clinical implications
PART II State-of-the-Science in Organ-Specific Biomarker Research
Genomic biomarkers of risk
Breast cancer development
Ductal carcinoma in situ (DCIS)
Lobular carcinoma in situ (LCIS)
Blood-based biomarkers for early detection
Current clinical practice
The challenge of tumor heterogeneity
Circulating tumor cells (CTC)
Prognostic tissue biomarkers of BBD and DCIS
Prognostic biomarkers of invasive carcinoma
Potential clinical applications of biomarkers for breast cancer
Improving risk assessment of healthy populations
Complementing mammographic screening
Secondary müllerian system
Heterogeneity of epithelial ovarian cancer
Early detection of ovarian cancer
Challenges for early detection of ovarian cancer
Two-stage screening strategies
Enhancing the first stage of a two-stage screening strategy
Enhancing the second stage of two-stage screening
9 Esophageal Cancer Biomarkers
Molecular alterations in pre-malignant and malignant disease of the esophagus
Early detection markers for Barretts esophagus (BE)
Aberrantly methylated genes
Biomarkers for predicting the risk of progression of BE to EAC
Biomarkers for prognosis and disease recurrence
Biomarkers to predict treatment response
Obstacles to the discovery of useful biomarkers for BE and esophageal cancer
10 Predictive Biomarkers for Therapy in Adenocarcinoma of the Upper Digestive Tract
Importance of biomarkers in adenocarcinoma of the upper digestive tract (UDT)
Predictive biomarkers in UDT adenocarcinoma
Excision repair cross-complementing 1 (ERCC1)
Chemotherapy-associated metabolism genes
ATP-binding cassette transporters (ABC transporters)
Germline alterations (single nucleotide polymorphisms (SNPs))
Currently targeted biomarkers in UDT adenocarcinoma
Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER 2)
Vascular endothelial growth factor (VEGF)
Other targets under development
New horizons in predictive biomarkers for adenocarcinoma of the UDT
Markers for cystic lesions
Investigational markers for PDA
Investigational markers for PDA
Importance of colorectal cancer screening
Current screening modalities
Desirable properties of biomarkers for screening/early detection of colorectal cancer
Biomarker discovery, verification and validation
Mass spectrometry protein profiling
13 Prognostic and Predictive Biomarkers for Colorectal Cancer
Definitions and types of biomarkers
Biomarkers of colorectal cancers (CRCS)
Race/ethnicity-based biomarkers
The metabolome as a source of biomarkers for CRCs
Genetic alterations as biomarkers
Challenges and future directions
14 Early Detection of Lung Cancer
The clinical context of early detection of lung cancer
Current status of early detection biomarkers for lung cancer
Current challenges in improving lung cancer diagnosis
Conclusions and future clinical perspectives
15 Commonalities in Lung Cancer and COPD
Natural history of COPD and lung cancer
Chronic obstructive lung disease (COPD)
Potential link between COPD and lung cancer
Commonalities in the molecular pathogenesis of lung cancer and COPD
Molecular field of injury
Challenges and future directions
US Food and Drug Administration (FDA) approved/cleared clinical diagnostic tests
[-2]proPSA and the Phi index
Prostate Cancer Antigen 3 (PCA3)
Clinical Laboratory Improvement Amendments (CLIA) and Laboratory Developed Test (LDT)
PART III Biomarkers, Screening and Precision Health: Implications for Public Health
17 Improving the Clinical Validity of Biomarker Research in Cancer Detection
Background, purpose and organization
Distinguishing clinical validity from analytical validity and clinical utility
Internal validity and external validity
Past lessons: CEA blood test for colon cancer
Recent lessons: proteomics blood tests for ovarian cancer
Later promising claims lead to an NCI study to assess clinical validity
NCIs study to assess clinical validity
Thinking big: using banked specimens in both discovery and validation
Practical issues I: how validity “gets in” to a study (design and conduct) and is measured (interpretation and reporting)
Practical issues II: how “valid” does a study need to be? And “when” or at what stage or phase is validity important – early (discovery) or late (“validation”)?
Challenge of addressing bias in observational research
Confusion caused by terminology: the “validation study”
“Validity” of discovery research
18 Cancer Overdiagnosis, Ramifications and Research Strategies
Population-level data supporting the overdiagnosis
Evidence for overdiagnosis from screening at individual disease sites
Cancer of the kidney and renal pelvis
Overdiagnosis of non-invasive, premalignant lesions
Why does overdiagnosis matter and what can we do about it?
19 Predictive Markers and Driver Genes From Treatment Trials: Potential Utility For Early Diagnosis
Common predictive markers
Minimally invasive technologies
Mutational landscape of driver genes in cancer
What are the predictive markers that are most likely to be useful for early diagnosis?
The PI3K/AKT/PTEN pathway
The RAS/RAF/MAPK/ERK pathway
20 Statistical Consideration in Predictive and Prognostic Markers
Biomarker identification and validation
Prognostic biomarkers versus predictive biomarkers
Regularized least squares regression models
Model validation and evaluation
Biomarker discover: challenges and obstacles
Data torture and multiple comparison problem
Reproducibility and generalizability
21 Clinical Validation of Molecular Biomarkers in Translational Medicine
Three stages of validation
Stage 1: identification, characterization, and evaluation (ICE)
Stage 2: data and model testing (DMT)
Stage 3: replication of results (ROR)
Issues related to validating biomarkers
Statistical model instability
Combining molecular biomarkers
Time denomination of the biomarker
22 Cancer Biomarker Assays: Performance Standards
Assay development: analytical performance
Specificity and analytical interference
Assay development: clinical performance
Clinical sensitivity and specificity
Positive and negative predictive values
23 Bioethics and Cancer Biomarker Research
Bioethics, ethics and the validation of cancer biomarkers
Case study: prostate specific antigen
Bioethical conclusions about validation
Data protection, confidentiality and the return of research results
24 Colon Cancer Screening
Molecular pathogenesis of colorectal cancer
Current screening practice methodologies: approaches and limitations
Screening recommendations according to risk stratification
Adoption of biomarkers in current screening practice: challenges and limitations
Biomarkers in Cancer Screening and Early Detection
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