Bunz Principles of Cancer Genetics

2. Auflage 2016
ISBN: 978-94-017-7484-0
Verlag: Springer Netherland
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 343 Seiten, eBook

Reihe: Biomedical and Life Sciences (R0)

This is the second edition of a widely used textbook that consolidates the basic concepts of the cancer gene theory and provides a framework for understanding the genetic basis of cancer. Particular attention is devoted to the origins of the mutations that cause cancer, and the application of evolutionary theory to explain how the cell clones that harbor cancer genes tend to expand. Focused on the altered genes and pathways that cause the growth of the most common tumors, Principles of Cancer Genetics is aimed at advanced undergraduates who have completed introductory coursework in genetics, biology and biochemistry, medical students and medical house staff. For students with a general interest in cancer, this book provides a highly accessible and readable overview. For more advanced students contemplating future study in the field of oncology and cancer research, this concise book will be useful as a primer.

Zielgruppe

Research

Autoren/Hrsg.

Bunz, Fred

Inhaltsverzeichnis

Preface Chapter 1: The Genetic Basis of CancerThe cancer gene theoryCancers are invasive tumorsCancer is a unique type of genetic diseaseWhat are cancer genes and how are they acquired?Mutations alter the human genomeGenes and mutationsSingle nucleotide substitutionsGene silencing is marked by cytosine methylation: epigeneticsEnvironmental mutagens, mutations and cancerInflammation promotes the propagation of cancer genesStem cells, Darwinian selection and the clonal evolution of cancersSelective pressure and adaptation: hypoxia and altered metabolismMultiple somatic mutations punctuate clonal evolutionTumor growth leads to cellular heterogeneityTumors are distinguished by their spectrum of driver gene mutations and passenger gene mutationsColorectal cancer: a model for understanding the process of tumorigenesisDo cancer cells divide more rapidly than normal cells?Germline cancer genes allow neoplasia to bypass steps in clonal evolutionCancer syndromes reveal rate-limiting steps in tumorigenesisThe etiologic triad: heredity, the environment, and stem cell divisionUnderstanding cancer genetics Chapter 2: OncogenesWhat is an oncogene?The discovery of transmissible cancer genesViral oncogenes are derived from the host genomeThe search for activated oncogenes: the RAS gene familyComplex genomic rearrangements: the MYC gene familyProto-oncogene activation by gene amplificationProto-oncogenes can be activated by chromosomal translocation Chromosomal translocations in liquid tumorsChronic myeloid leukemia and the Philadelphia chromosomeOncogenic activation of transcription factors in Prostate cancer and Ewing’s sarcoma Oncogene discovery in the genomic era: mutations in PIK3CA Selection of tumor-associated mutationsMultiple modes of proto-oncogene activationOncogenes are dominant cancer genesGermline mutations in RET and MET confer cancer predispositionProto-oncogene activation and tumorigenesis Chapter 3: Tumor Suppressor GenesWhat is a tumor suppressor gene?The discovery of recessive cancer phenotypesRetinoblastoma and Knudson’s two-hit hypothesisChromosomal localization of the retinoblastoma geneThe mapping and cloning of the retinoblastoma gene Tumor suppressor gene inactivation: the second ‘hit’ and loss of heterozygosityRecessive genes, dominant traitsAPC inactivation in inherited and sporadic colorectal cancersTP53 inactivation: a frequent event in tumorigenesis Functional inactivation of p53: tumor suppressor genes and oncogenes interactMutant TP53 in the germline: Li Fraumeni syndromeGains-of-function caused by cancer-associated mutations in TP53Cancer predisposition: allelic penetrance, relative risk and the odds ratioBreast cancer susceptibility: BRCA1 and BRCA2Genetic losses on chromosome 9: CDKN2AComplexity at CDKN2A: neighboring and overlapping genesGenetic losses on chromosome 10: PTENSMAD4 and the maintenance of stromal architectureTwo distinct genes cause neurofibromatosisFrom flies to humans, Patched proteins regulate developmental morphogenesisvon Hippel-Lindau diseaseNOTCH1: tumor suppressor gene or oncogene?Multiple endocrine neoplasia type 1Most tumor suppressor genes are tissue-specific Modeling cancer syndromes in miceGenetic variation and germline cancer genesTumor suppressor gene inactivation during colorectal tumorigenesisInherited tumor suppressor gene mutations: gatekeepers and landscapersMaintaining the genome: caretakers  Chapter 4: Genetic Instability and CancerWhat is genetic instability?The majority of cancer cells are aneuploidAneuploid cancer cells exhibit chromosome instabilityChromosome instability arises early in colorectal tumorigenesisChromosomal instability accelerates clonal evolutionAneuploidy can result from mutations that directly impact mitosisSTAG2 and the cohesion of sister chromatidsOther genetic and epigenetic causes of aneuploidyTransition from tetraploidy to aneuploidy during tumorigenesis Multiple forms of genetic instability in cancerDefects in mismatch repair cause hereditary nonpolyposis colorectal cancerMismatch repair-deficient cancers have a distinct spectrum of mutationsDefects in nucleotide excision repair cause xeroderma pigmentosumNER syndromes: clinical heterogeneity and pleiotropyDNA repair defects and mutagens define two steps towards genetic instabilityDefects in DNA crosslink repair cause Fanconi anemiaA defect in DNA double strand break responses causes ataxia-telangiectasiaA unique form of genetic instability underlies Bloom syndrome Aging and cancer: insights from the progeroid syndromesInstability at the end: telomeres and telomeraseOverview: genes and genetic stability Chapter 5: Cancer GenomesDiscovering the genetic basis of cancer: from genes to genomesWhat types of genetic alterations are found in tumor cells?How many genes are mutated in the various types of cancer?What is the significance of the mutations that are found in cancers?When do cancer-associated mutations occur?How many different cancer genes are there? How many cancer genes are required for the development of cancer?Cancer genetics shapes our understanding of metastasisTumors are genetically heterogenousBeyond the exome: the ‘dark matter’ of the cancer genomeA summary: the genome of a cancer cell Chapter 6: Cancer Gene PathwaysWhat are cancer gene pathways?Cellular pathways are defined by protein-protein interactionsIndividual biochemical reactions, multistep pathways, and networksProtein phosphorylation is a common regulatory mechanism Signals from the cell surface: protein tyrosine kinases Membrane-associated GTPases: the RAS pathwayAn intracellular kinase cascade: the MAPK pathwayGenetic alterations of the RAS pathway in cancer Membrane-associated lipid phosphorylation: the PI3K/AKT pathwayControl of cell growth and energetics: the mTOR pathway Genetic alterations in the PI3K/AKT and mTOR pathways define roles in cell survivalThe STAT pathway transmits cytokine signals to the cell nucleusMorphogenesis and cancer: the WNT/APC pathwayDysregulation of the WNT/APC pathway in cancersNotch signaling mediates cell-to-cell communicationMorphogenesis and cancer: the Hedgehog pathwayTGF-/ SMAD signaling maintains adult tissue homeostasisMYC is a downstream effector of multiple cancer gene pathways activation is triggered by damaged or incompletely replicated chromosomes p53 is controlled by protein kinases encoded by tumor suppressor genesp53 induces the transcription of genes that suppress cancer phenotypesFeedback loops dynamically control p53 abundance The DNA damage signaling network activates interconnected repair pathwaysInactivation of the pathways to apoptosis in cancerRB1 and the regulation of the cell cycleSeveral cancer gene pathways converge on cell cycle regulatorsMany cancer cells are cell cycle checkpoint-deficientChromatin modification is recurrently altered in many types of cancerSummary: putting together the puzzle  Chapter 7: Genetic Alternations in Common CancersCancer genes cause diverse diseasesCancer incidence and prevalenceLung cancerProstate cancerBreast cancerColorectal cancerEndometrial cancerMelanoma of the skinBladder cancerLymphomaCancers in the kidneyThyroid cancerLeukemiaCancer in the pancreasOvarian cancerCancers of the oral cavity and pharynxLiver cancerCancer of the uterine cervixStomach cancerBrain tumors Chapter 8: Cancer Genetics in the ClinicThe uses of genetic informationElements of cancer risk: carcinogens and genes Identifying carriers of germline cancer genesCancer genes as biomarkers of early stage malignancies Cancer genes as biomarkers for diagnosis, prognosis and recurrenceConventional anticancer therapies inhibit cell growthExploiting the loss of DNA repair pathways: synthetic lethalityOn the horizon: achieving synthetic lethality in TP53-mutant cancersMolecularly targeted therapy: BCR-ABL and imatinibClonal evolution of therapeutic resistanceTargeting EGFR mutationsAntibody-mediated inhibition of receptor tyrosine kinasesInhibiting Hedgehog signalingA pipeline from genetically-defined targets to targeted therapies Neoantigens are recognized by the immune systemThe future of oncology Index

Über Autor(innen)

Fred Bunz, M.D., Ph.D is a native of Long Beach, New York. He attended Stony Brook University and graduated from its Medical Scientist Training Program. His doctoral research in the enzymology of human DNA replication was conducted at Cold Spring Harbor Laboratory. Dr. Bunz completed a postdoctoral fellowship in Cancer Genetics at The Johns Hopkins University and the Howard Hughes Medical Institute, and now heads a laboratory at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins that is focused on understanding the effects of DNA damage on cancer cells and normal cells. He lives in Baltimore with his wife, two children, a cat, and an Old English Sheepdog.