Genomic Medicine. A Practical Guide

Preface
Contents
Contributors
Part I: General Concepts
	Chapter 1: Pre-analytics, Current Testing Technologies, and Limitations of Testing
		Introduction
		Pre-analytic Variables in Surgical Pathology
			Prefixation
			Fixation
			Decalcification
			Processing and Storage
			Tissue Stewardship
			RNA Pre-analytic Considerations
			Pre-analytics of Circulating Tumor DNA or Cell-Free DNA
		Landscape of Current Testing Technologies
			Tests to Detect Chromosomal Abnormalities
				Karyotyping (G-Banding)
				Fluorescence In Situ Hybridization
				Reverse Transcription Polymerase Chain Reaction
				Multiplex Ligation-Dependent Probe Amplification
				Array Comparative Genomic Hybridization (aCGH) and Single-Nucleotide Polymorphism (SNP) Arrays
			Methods Used to Detect Changes in the DNA Sequence
				Allele-Specific PCR
				Sanger Sequencing with Capillary Electrophoresis
				Pyrosequencing
				Melting Curve Analysis
				Next-Generation Sequencing
		Gene Expression Profiling
		References
	Chapter 2: Next-Generation Sequencing
		Introduction
		Library Preparation
			Nucleic Acid Isolation
			Fragmentation
			End Repair
			Adapter Ligation
			Size Selection
			Target Enrichment
			Amplification
			Quantitation and Quality Assessment
			Library Pooling
			Additional Steps
		Sequencing
			Short-Read Sequencers (<1000 Nucleotides)
			Long-Read Sequencing (>1000 Nucleotides)
		Informatics Process
			Base Calls
			Demultiplexing
			FASTQ Files
			Sequence Assembly
			Alignment
			Variant Calling
			Variant Filtering
			Variant Annotation
			Variant Prioritization
			Clinical Reporting
			Flow and Storage of Data
		Clinical Applications of NGS
		Conclusion
		References
	Chapter 3: Cell-Free DNA Testing
		Introduction
		Current Applications: Noninvasive Prenatal Testing
		Current Applications: Solid Organ Transplantation
		Current Applications: Cancer
		Pre-analytical Considerations
			cfDNA Biology
			Specimen Type
			Collection and Processing
		cfDNA Detection and Quantification Technologies
		Limitations
		Future Directions
		References
	Chapter 4: Role of Bioinformatics in Molecular Medicine
		Introduction
		Central Dogma of NGS Bioinformatics
			FASTA/FASTQ
			Alignment
			BAM/SAM
			Variant Calling
			Variant Call Format (VCF) File
			Variant Annotation and Prioritization
		Regulatory Considerations
		Advanced Applications
			Copy Number Alterations
			Structural Variants
			Microsatellite Instability
		References
	Chapter 5: Interpreting Genomic Reports
		Introduction
		Reporting Sequence Variants
			Elements of the Molecular Pathology Report
			Elements Unique to Genomic Reports
		Variant Categorization
			Gene and Sequence Variant Nomenclature
			Mutation, Polymorphism, and Variants
				Interpretation
				Germline Variants
				Somatic Variants
		References
Part II: Applications in Solid Tumors
	Chapter 6: Lung Carcinoma
		Introduction
		Alterations with Already Approved Targeted Therapies
			EGFR Mutations
			ALK Fusions
			ROS1 Fusions
			BRAF Mutations
			NTRK Fusions
			KRAS Mutations
			HER2 Mutations
			MET Alterations
			RET Fusions
			PIK3CA Mutations
			MAP2K1/MEK1 Mutations
			FGFR3 Alterations
		Acquired Resistance Mechanisms to TKIs
		Molecular Testing Guidelines for Therapy Selection
		Conclusions
		References
	Chapter 7: GI Including GIST
		Introduction
		Microsatellite Instability in Colorectal and Gastric Adenocarcinomas
			MLH1 Promoter Hypermethylation in CRC
			RAS Mutations in CRC
			BRAF Alterations in CRC
			HER2 Alterations in Upper Gastrointestinal Adenocarcinomas and CRC
			PIK3CA Mutations in CRC
		Other Emerging Biomarkers in CRC and Upper Gastrointestinal Adenocarcinomas
			MET Amplification
			EGFR Alterations
			MAP2K1 Mutations
			FGFR Alterations
			NTRK Rearrangements
			RET, ALK, and ROS1 Rearrangements
		Mutational Testing in Gastrointestinal Stromal Tumors
			KIT and PDGFRA Mutant GISTs
			KIT/PDGFRA-Negative GISTs
		Molecular Testing for Familial Syndromes
		References
	Chapter 8: Breast
		Introduction
		Molecular Diagnostics in Breast Cancer
		Resistance Mechanisms in Breast Cancer
		For the Practicing Clinician
		References
	Chapter 9: Genitourinary Tumors
		Introduction
		Prostate
			Molecular Diagnostics in Prostate Cancer
				Prognostic Molecular Assays in PCa
				Targets of Therapy and Predictive Molecular Markers
		Bladder
			Molecular Diagnostics in Bladder Cancer
				Diagnostic Assays
				Genomic Taxonomy, Targets of Therapy, and Predictive Markers
		References
	Chapter 10: Gynecologic Malignancies
		Introduction
		Ovary
		Endometrial Cancer
		Uterine Mesenchymal Tumors
		References
	Chapter 11: Sarcomas
		Introduction
			Sarcomas with Recurrent Translocations (Table 11.1)
			Benign Mesenchymal Neoplasms with Recurrent Translocations (Table 11.2)
			Adipocytic Neoplasms (Tables 11.3 and 11.4)
			Vascular Tumors (Table 11.5)
			Tumors with Recurrent Gene Fusions (Including EWSR1) and Other Alterations (Tables 11.6, 11.7, 11.8, 11.9, 11.10, 11.11, and 11.12)
		Selected References
	Chapter 12: Salivary Gland Carcinomas
		Introduction
		Mucoepidermoid Carcinoma
			Phenotype
			Genetics and Clinical Utility
		Adenoid Cystic Carcinoma
			Phenotype
			Genetics and Clinical Utility
		Secretory Carcinoma of Salivary Gland
			Phenotype
			Genetics and Clinical Utility
		Clear Cell Carcinoma
			Phenotype
			Genetics and Clinical Utility
		Myoepithelial Carcinoma
			Phenotype
			Genetics and Clinical Utility
		Polymorphous Adenocarcinoma and Cribriform Adenocarcinoma of Minor Salivary Gland
			Phenotype
			Genetics and Clinical Utility
		Salivary Duct Carcinoma
			Phenotype
			Genetics and Clinical Utility
		Intraductal Carcinoma
			Phenotype
			Genetics and Clinical Utility
		References
	Chapter 13: Sinonasal Carcinomas
		Introduction
		NUT Carcinoma
			Phenotype
			Genetics and Clinical Utility
		SMARCB1-Deficient Sinonasal Carcinoma
			Phenotype
			Genetics and Clinical Utility
		Sinonasal Undifferentiated Carcinoma and Large Cell Neuroendocrine Carcinoma
			Phenotype
			Genetics and Clinical Utility
		Sinonasal Squamous Cell Carcinomas and Adenocarcinomas with Genetic Signatures
		References
Part III: Applications in Hematopathology
	Chapter 14: Acute Myeloid Neoplasms
		Introduction
		A Standard Genetic Workup
		AML with Recurrent Genetic Aberrancies
			Core Binding Factor AML (Tables 14.2 and 14.3)
			Acute Promyelocytic Leukemia (APL) (Table 14.4)
			AML with t(9;11)(p21.3;q23.3), KMT2A-MLLT3 (Table 14.5)
			AML with t(6;9)(p23;q34.1), DEK-NUP214 (Table 14.6)
			AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM (Table 14.7)
			AML (Megakaryoblastic) with t(1;22)(p13.3;q13.1), RBM15-MRTFA (Table 14.8)
			AML with Mutated NPM1 (Table 14.9)
			AML with Biallelic Mutations of CEBPA (Table 14.10)
			Provisional 2016 WHO AML with Recurrent Genetic Abnormality Subtypes
		AML with Myelodysplasia-Related Changes
		Therapy-Related Myeloid Neoplasms
		Myeloid Neoplasms with Germline Predisposition and AML in Children
			Myeloid Neoplasms with Germline Predisposition
			Transient Abnormal Myelopoiesis and Myeloid Leukemia Associated with Down Syndrome
			Childhood AML
		References
	Chapter 15: Chronic Myeloid Neoplasms
		Introduction
		Myeloproliferative Neoplasms (MPNs)
		Mastocytosis
		Myeloid/Lymphoid Neoplasms with Eosinophilia and Gene Rearrangements
		Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)
		Myelodysplastic Syndrome (MDS)
		References
	Chapter 16: Lymphomas
		Introduction
		Recurrent Molecular Aberrancies in B-Cell Neoplasms
			Hodgkin Lymphoma (HL)
			Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
			Mantle Cell Lymphoma (MCL)
			Extranodal Marginal Zone Lymphoma (Extranodal MZL, Mucosa-Associated Lymphoid Tissue Lymphoma, MALT)
			Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia (LPL/WM)
			Hairy Cell Leukemia (HCL)
			Follicular Lymphoma (FL)
			Diffuse Large B-Cell Lymphoma (DLBCL) and Other High-Grade B-Cell Lymphomas (HGBCL)
			Burkitt’s Lymphoma (BL)
		Recurrent Molecular Aberrancies in T-Cell Neoplasms
			Angioimmunoblastic T-Cell Lymphoma (AITL) and Other Nodal T-Cell Lymphomas with T-Follicular Helper (TFH) Phenotype
			Anaplastic Large-Cell Lymphoma (ALCL)
			Peripheral T-Cell Lymphoma, Not Otherwise Specified (PTCL, NOS)
			T-Cell Large Granular Lymphocytic (T-LGL) Leukemia
			T-Cell Prolymphocytic Leukemia (T-PLL)
			Enteropathy-Associated T-Cell Lymphoma (EATL) and Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma (MEITL)
			Adult T-Cell Leukemia/Lymphoma (ATLL)
			Extranodal Natural Killer/T-Cell Lymphoma (ENKTL)
		References
Index