Diagnostic Molecular Pathology

A Guide to Applied Molecular Testing

2nd Edition - October 18, 2023
Editors: William B. Coleman, Gregory J. Tsongalis
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 8 2 2 8 2 4 - 1
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 2 2 9 9 3 - 4

Diagnostic Molecular Pathology: A Guide to Applied Molecular Testing, Second Edition assembles a group of experts to discuss the molecular basis and mechanisms of major human… Read more

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Diagnostic Molecular Pathology: A Guide to Applied Molecular Testing, Second Edition assembles a group of experts to discuss the molecular basis and mechanisms of major human diseases and disease processes and how the molecular features of disease can be harnessed to develop practical molecular tests for disease detection, diagnosis and prognosis. The book explains how molecular tests are utilized in the treatment of patients in personalized medicine, highlights new technologies and approaches of applied molecular pathology, and discusses how this discovery-based research yields new and useful biomarkers and tests.

As it is essential to stay up-to-date on new molecular diagnostics in this changing field, this book covers critically important areas in the practice of personalized medicine and reflects our understanding of the pathology, pathogenesis and pathophysiology of human disease.

Cover image
Title page
Table of Contents
Copyright
Dedication
List of contributors
Preface
Chapter 1. Introduction to molecular testing in human disease
Abstract
Introduction
Mutations and epimutations
Sources of nucleic acids for molecular testing
Classification of disease
Molecular classification of disease
Molecular testing and companion diagnostics
Molecular detection of disease
Molecular diagnosis of disease
Molecular prognostication of disease
Perspectives
References
Chapter 2. Laboratory approaches in molecular pathology: the polymerase chain reaction
Abstract
Introduction
The polymerase chain reaction
Components of the polymerase chain reaction
Optimization of polymerase chain reaction amplification reactions
Increasing polymerase chain reaction specificity and sensitivity
Polymerase chain reaction contaminants
Inhibitors of polymerase chain reaction
Analysis of polymerase chain reaction products
Variations of the typical polymerase chain reaction amplification reaction
References
Chapter 3. Whole-exome and whole-genome sequencing in the molecular diagnostic laboratory
Abstract
Introduction
Molecular technology in next-generation sequencing
Clinical utility of clinical genome sequencing
Applications of whole-genome sequencing
Optimism surrounding whole-genome sequencing
References
Chapter 4. Long-read sequencing for metagenomics in microbiology
Abstract
Introduction
Summary
Disclosure
References
Chapter 5. Molecular testing for human immunodeficiency virus
Abstract
Introduction
Background on human immunodeficiency virus infection and AIDS
Molecular tools in the diagnosis and follow-up of human immunodeficiency virus infection
Special emphasis on the use of human immunodeficiency virus molecular tools in specific clinical situations
New insights in molecular human immunodeficiency virus testing
Conclusion
References
Chapter 6. Molecular testing in hepatitis virus-related disease
Abstract
Introduction
Hepatitis A virus and hepatitis A virus RNA detection
Hepatitis B virus infection
Hepatitis C virus infection and hepatitis C virus RNA detection
Hepatitis D virus and hepatitis D virus RNA detection
Hepatitis E virus and detection of hepatitis E virus RNA
Hepatitis G virus and its genome
Summary
References
Chapter 7. Molecular testing for human papillomaviruses
Abstract
Introduction
Molecular target
Molecular technologies
Clinical utility
Limitations
References
Chapter 8. Molecular testing for parvoviruses
Abstract
The family Parvoviridae
Parvovirus B19
Molecular target
Molecular technologies
Clinical utility
Other parvoviruses
References
Chapter 9. Molecular testing for polyoma viruses
Abstract
Introduction
Molecular targets
Molecular technologies
Clinical utility
Limitations of testing
References
Chapter 10. Molecular testing for respiratory viruses
Abstract
Introduction
Viral pathogens targeted by molecular testing
Clinical utility of molecular diagnostics for respiratory virus infection
Molecular technologies and limitations of testing
Conclusions
Acknowledgments
References
Chapter 11. Molecular testing for diseases associated with bacterial infections
Abstract
Introduction
Identification of bacteria
Respiratory infections
Gastrointestinal infections
Bloodstream infections
Group B Streptococcus screening
Future perspectives
Acknowledgments
References
Chapter 12. Agents associated with sexually transmitted infections
Abstract
Introduction
Syphilis
Gonorrhea
Genital chlamydia infection
Mycoplasma genitalium infection
Trichomoniasis
Future directions
Concluding remarks
References
Chapter 13. Molecular methods for healthcare-acquired infections
Abstract
Introduction
Methicillin-resistant Staphylococcus aureus molecular diagnostic testing and clinical utility
Methicillin-resistant Staphylococcus aureus molecular typing and clinical utility
Methicillin-resistant Staphylococcus aureus molecular screening/surveillance
Clostridioides difficile
Clostridioides difficile molecular testing and clinical utility
Clostridioides difficile molecular typing and clinical utility
Conclusions
References
Chapter 14. Molecular testing in emerging infectious diseases
Abstract
Background and catalog of emerging infectious agents
Discovery of emerging infectious agents using molecular methods
Molecular epidemiological studies of emerging infectious pathogens
Molecular diagnostics of emerging infectious pathogens
Limitations of current testing and future prospects
References
Chapter 15. Molecular and serological testing in the setting of a global pandemic
Abstract
Introduction
Historical overview
Molecular diagnostic tests for SARS-CoV-2/COVID-19
Serological testing
Surveillance of SARS-CoV-2 variants of concern
SARS-CoV-2 infection in tissues
RNA ISH
Regulation and reimbursement for COVID-19 testing
Vaccine development for management of COVID-19
Summary
References
Chapter 16. Noninvasive prenatal screening for fetal aneuploidies
Abstract
Introduction
The molecular target: approaches using plasma nucleic acids
Molecular technologies and clinical utility: four approaches by four commercial laboratories
Limitations of testing
Conclusions and future directions
References
Chapter 17. Molecular testing in inherited cardiomyopathies
Abstract
Introduction
Major forms of cardiomyopathy
Molecular target
Molecular technologies
Clinical utility
Limitations of testing
Abbreviations
References
Chapter 18. Molecular diagnostics for coagulopathies
Abstract
Introduction
Molecular targets
Coagulopathy-associated genes
Clinical utility
Limitations of testing
References
Chapter 19. Molecular diagnosis of cystic fibrosis
Abstract
Introduction
Molecular target
Molecular technologies
Clinical utility
Limitations of testing
References
Chapter 20. Molecular testing in hemochromatosis
Abstract
Introduction
Background on disease mechanisms
Clinical strategy leading to diagnosis of hemochromatosis
Clinical strategy for molecular testing in family screening
Molecular biology methods and strategy
Perspectives
Conclusions
References
Chapter 21. Molecular genetics of spinal muscular atrophy
Abstract
Introduction
Clinical presentation
Molecular targets
Molecular technologies
Clinical utility
Limitations of testing
Conclusions
References
Chapter 22. Molecular testing in autism spectrum disorder
Abstract
Introduction
Behavioral diagnosis of autism spectrum disorders
Comorbidities associated with autism spectrum disorder including syndromes
Genetic categories of autism spectrum disorder
Genetic investigation of individuals with autism spectrum disorder
Considerations for an autism-relevant gene list
Clinical utility
Limitations of testing
Conclusions
References
Chapter 23. Molecular testing in breast cancer
Abstract
Introduction
HER2 testing by fluorescence in situ hybridization
Breast cancer molecular subtype
Prognostic signatures and prediction of benefit from therapy
References
Chapter 24. Molecular testing in lung cancer
Abstract
Introduction
Molecular targets
Anaplastic lymphoma kinase
Molecular technologies
Limitations of testing
Clinical utility
Acknowledgment
References
Chapter 25. Molecular testing in colorectal cancer
Abstract
Introduction
Molecular targets
Biomarkers for targeted therapies in colorectal cancer
Biomarkers for immune checkpoint inhibitor therapies
Molecular technologies, clinical utility, and limitations of testing
References
Chapter 26. Molecular pathology and testing in melanocytic tumors
Abstract
Introduction
Molecular testing for the diagnostician
Genetic testing for the diagnostician
Molecular pathology of melanoma for the researcher
Genomic alterations in melanoma
Tissue microenvironment changes and melanoma
Important proteins in melanoma and possible directions for future research
Technologies used to interrogate the molecular pathology of melanoma
Conclusion
References
Chapter 27. Molecular testing for gliomas
Abstract
Introduction
Molecular target
Molecular technologies
Clinical utility
Limitations of testing
References
Chapter 28. Molecular testing in pancreatic cancer
Abstract
Introduction
Pancreatic ductal adenocarcinoma biomarkers in serum
Pancreatic ductal adenocarcinoma biomarkers in pancreatic juice
Pancreatic ductal adenocarcinoma biomarkers in stool
Pancreatic ductal adenocarcinoma biomarkers in urine
Pancreatic ductal adenocarcinoma biomarkers in saliva
Summary
References
Chapter 29. Molecular testing in gynecologic cancer
Abstract
Background
Human papilloma virus and uterine cervical cancer
Gestational trophoblastic disease
Endometrial stromal sarcoma
Sex cord stromal tumors: adult granulosa cell tumor and sertoli-leydig cell tumor
Lynch syndrome screening in endometrial cancer
Tumors of the gynecologic tract with switch/sucrose nonfermenting protein family alterations
Future directions in gynecologic cancer: using genomic data and theranostic testing to improve diagnostic classification
References
Chapter 30. The emerging genetic landscape of renal cell carcinoma
Abstract
Introduction
Molecular targets and technologies
Clinical utility
Limitations of testing
Acknowledgment
References
Chapter 31. Molecular testing in thyroid cancer
Abstract
Introduction
Molecular alterations in thyroid cancer
Molecular technologies
Clinical utility of molecular testing
Limitations of testing
References
Chapter 32. Molecular testing in pediatric cancers
Abstract
Introduction
Retinoblastoma
Wilms tumor
Neuroblastoma
References
Chapter 33. Molecular pathogenesis of soft tissue and bone tumors
Abstract
Glossary
Introduction
Selected soft tissue tumors
Selected bone tumors
References
Chapter 34. Molecular pathology of gastrointestinal stromal tumors
Abstract
Introduction
Molecular mechanisms of gastrointestinal stromal tumor
New developments and future directions
References
Chapter 35. Molecular pathology of hepatocellular carcinoma
Abstract
Introduction
Molecular mechanisms of hepatocellular carcinoma
New developments
References
Chapter 36. Molecular testing in myeloproliferative neoplasms
Abstract
Introduction
Clinical features and molecular pathogenesis of myeloproliferative neoplasms
Molecular testing in myeloproliferative neoplasms
Molecular methods for myeloproliferative neoplasm testing
Conclusion
References
Chapter 37. Molecular testing in myelodysplastic syndromes
Abstract
Introduction
Cytogenetic findings in myelodysplastic syndrome
Gene mutations in myelodysplastic syndrome
Clonal hematopoiesis
Role of sequencing in diagnosis of myelodysplastic syndrome
Prognostic markers in myelodysplastic syndrome
Conclusion
References
Chapter 38. Molecular testing in acute myeloid leukemia
Abstract
Abbreviations
Introduction
Diagnostic workup of acute myeloid leukemia
Cytogenetic abnormalities in acute myeloid leukemia
Gene mutations in acute myeloid leukemia
Monitoring residual disease
New horizons
References
Chapter 39. Molecular testing in the assessment of bone marrow transplant engraftment
Abstract
Introduction
Molecular target
Molecular technologies
Clinical utility
Limitations of testing
References
Chapter 40. Pharmacogenomics in cardiovascular disease
Abstract
Introduction
Clopidogrel
Conclusion and future perspective
Warfarin
Statins
Metoprolol
Antiarrhythmics
Conclusion and future perspective
Disclosures
References
Chapter 41. Personalized medicine for disorders of hemostasis and thrombosis
Abstract
Introduction
Bleeding disorders
Thrombotic disorders
Personalizing the care of patient with disorders of hemostasis and thrombosis
Summary
References
Chapter 42. Germline pharmacogenomics in cancer treatment
Abstract
Introduction
Molecular target: fluoropyrimidines and DPYD
Molecular target: irinotecan and UGT1A1
Molecular target: rasburicase and G6PD deficiency
Molecular target: tamoxifen and CYP2D6
Molecular target: thiopurines and TPMT/NUDT15
Other considerations for personalized medicine in cancer treatment
References
Chapter 43. Imaging mass spectrometry in clinical pathology
Abstract
Introduction
Imaging mass spectrometry
Applications to anatomic pathology
Advances in imaging mass spectrometry
Conclusions
References
Chapter 44. Artificial intelligence and deep learning in molecular testing
Abstract
Introduction
Introduction to machine learning
Training and evaluating a machine learning algorithm and example code
Emerging areas of application in molecular pathology
Challenges and opportunities facing the adoption of artificial intelligence technologies in molecular pathology
Conclusion
Acknowledgments
Appendix
References
Chapter 45. Nanotechnology for molecular diagnostics
Abstract
Introduction
Clinical utility of nanotechnology
Nanotechnology for enrichment
Nanotechnology for nucleic acid amplification and detection
Nanotechnology for sequencing
Nanotechnology for multiplexed cell and tissue profiling
Advantages and limitations of nanotechnology
Conclusion
References
Chapter 46. Chip-based nanotechnology in the molecular pathology laboratory and beyond
Abstract
Introduction
Today’s diagnostic workhorses
A lesson learned from COVID-19: the need for point-of-care testing
Nanoparticle-driven detection modalities
Applications of electrochemistry in pathogen detection
Multiplexing
Conclusions and perspective
Acknowledgments
References
Chapter 47. Translational and clinical applications of the GeoMx digital spatial profiling platform
Abstract
List of abbreviations
Spatial biology and introduction to technology
Clinical opportunities
Translational applications
Biomarker discovery in triple-negative breast cancer
Future of Digital Spatial Profiler clinical assays
Panel design
Evaluating assay performance
Assay signature development
Assay procedures and output
Analysis and clinical best practices
Conclusion
Acknowledgments
Funding information
Disclaimer
Conflict of interest
References
Index

William B. Coleman

William B. Coleman, PhD is the Executive Officer for the American Society for Investigative Pathology (Rockville, MD). Prior to taking this position with the American Society for Investigative Pathology, Dr. Coleman spent 28 years at the University of North Carolina School of Medicine (Chapel Hill, NC), first as a postdoctoral fellow (1990-1995) and then as a faculty member (1995-2018) in the Department of Pathology and Laboratory Medicine. During his time at the UNC School of Medicine, Dr. Coleman served as Director of Graduate Studies for the Molecular and Cellular Pathology Ph.D. Program (2006-2012; now the Pathobiology and Translational Medicine Ph.D. Program), was a co-founder of the UNC Program in Translational Medicine and served as its Co-Director (2006-2015) and then its Director (2015-2018), was affiliated with the Curriculum in Toxicology, the Cancer Biology Training Program, and was a member of the UNC Lineberger Comprehensive Cancer Center. Dr. Coleman was active in teaching biomedical graduate students and is a four-time recipient of the Joe W. Grisham Award for Excellence in Graduate Student Teaching from the Molecular and Cellular Pathology graduate students at the UNC School of Medicine. Prior to becoming an employee, Dr. Coleman was active in the leadership of the American Society for Investigative Pathology, serving in various roles including President (2015-2016). Dr. Coleman was honored with the ASIP Outstanding Investigator Award in 2013 from the American Society for Investigative Pathology. He is also a long-time member of the American Association for Cancer Research. He serves as Senior Associate Editor for The American Journal of Pathology, and is an Associate Editor for BMC Cancer, and PLoS One, and serves on the editorial boards of Clinica Chimica Acta, Experimental and Molecular Pathology, Archives of Pathology and Laboratory Medicine, Laboratory Investigation, and Current Pathobiology Reports, and has served as an ad hoc reviewer for 99 other journals. Dr. Coleman’s major research interests are in the molecular pathogenesis of human cancers, with a specific interest in breast cancer epigenetics, liver carcinogenesis, and lung cancer biology. His research was funded by the NIH/NCI, The Susan G. Komen Breast Cancer Foundation, Friends for an Earlier Breast Cancer Test, and the UNC Lineberger Comprehensive Cancer Center. Dr. Coleman is the author of over 140 original research articles, reviews, and book chapters. In addition, Dr. Coleman has co-edited or co-authored ten books on topics related to molecular pathology, molecular diagnostics, and the molecular pathogenesis of human cancer.

Affiliations and expertise

Executive Officer, American Society for Investigative Pathology, Rockville, MD, USA

Gregory J. Tsongalis

Gregory J. Tsongalis, PhD, HCLD, CC, FNACB., is the Vice Chair for Research and the Director of the Laboratory for Clinical Genomics and Advanced Technology (CGAT) in the Department of Pathology and Laboratory Medicine at the Dartmouth-Hitchcock Medical Center and Norris Cotton Cancer Center (NCCC) in Lebanon, NH. He is a Professor of Pathology and Laboratory Medicine at the Audrey and Theodor Geisel School of Medicine at Dartmouth in Hanover, NH and a member of the NCCC Molecular Therapeutics Program and the gastrointestinal and breast cancer clinical oncology groups. In 2016 he became a member of Dartmouth College’s Program in Experimental and Molecular Medicine (PEMM), and he has served on the advisory board of the Health Care Genetics Professional Science Master’s Degree Program and Diagnostic Genetic Sciences Program at the University of Connecticut (Storrs, CT). His area of expertise is in the development and implementation of clinical molecular diagnostic technologies. His research interests are in the pathogenesis of human cancers, personalized medicine and disruptive technologies. He has authored/edited twelve textbooks in the field of molecular pathology, published more than 230 peer reviewed manuscripts, and has been an invited speaker at both national and international meetings. He has served on numerous committees of the American Association for Clinical Chemistry, the American Society for Investigative Pathology, the Federation for American Societies for Experimental Biology, and the Association for Molecular Pathology (where he is a past President). He is active in the Alliance for Clinical Trials in Oncology, the Association for Molecular Pathology, the American Association for Clinical Chemistry, the American Association of Bioanalysts, and the American Society for Investigative Pathology. He serves on the editorial boards of 8 journals including Clinical Chemistry, Experimental and Molecular Pathology, and the Journal of Molecular Diagnostics. In 2016, Dr. Tsongalis received the Norris Cotton Cancer Center Award for Excellence, in 2017 the Association for Molecular Pathology (AMP) Jeffrey A. Kant Leadership Award, and in 2019 the American Society for Investigative Pathology Robbins Distinguished Educator Award. He also serves on numerous corporate scientific advisory boards.

Affiliations and expertise

Laboratory for Clinical Genomics and Advanced Technology (CGAT), Department of Pathology and Laboratory Medicine, Dartmouth, Hitchcock Medical Center and Dartmouth Cancer Center, Lebanon, NH, United States and the Geisel School of Medicine at Dartmouth, Hanover, NH, USA

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

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