Genomic Medicine. A Practical Guide

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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) 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