Cancer genetics is a field of daunting breadth and depth. The literature describes hundreds of genes and genetic alterations that are variably associated with again as many disease states and risk factors. Integrating these disparate pieces of highly specialized information is challenging for the professional scientist and student alike. This book consolidates the main concepts of the cancer gene theory, and provides a framework for understanding the genetic basis of cancer.
Focused on the most highly representative genes that underlie the most common cancers, the book is aimed at advanced undergraduates who have completed introductory courses in genetics, biology and biochemistry, medical students, and house medical house staff preparing for board examinations.
Primary attention is devoted to the origins of cancer genes and the application of evolutionary theory to explain why the cell clones that harbor cancer genes tend to expand. The many points of controversy in cancer research are avoided, in favor of firmly established concepts. This book does not delve into tumor pathobiology beyond what is required to understand the role of genetic alterations in neoplastic growth.
Table of contents
Chapter 1: The Genetic Basis of Cancer
The cancer gene theory
Cancers are invasive tumors
Cancer is a unique type of genetic disease
What are cancer genes and how are they acquired?
Mutations alter the human genome
Genes and mutations
Genetic variation and cancer genes
Which mutations are important in cancer?
Single nucleotide substitutions
Gene silencing by cytosine methylation: epigenetics
Environmental mutagens, mutations and cancer
Inflammation promotes the propagation of cancer genes
Darwinian selection and the clonal evolution of cancers
Selective pressure and adaptation: hypoxia and altered metabolism
Multiple somatic mutations punctuate clonal evolution
How many mutations contribute to a cancer?
Colorectal cancer: a model for understanding the process of tumorigenesis
Do cancer cells divide more rapidly than normal cells?
Germline cancer genes allow neoplasia to bypass steps in clonal evolution
Cancer syndromes reveal rate-limiting steps in tumorigenesis
Understanding cancer genetics
Chapter 2: Oncogenes
What is an oncogene?
The discovery of transmissible cancer genes
Viral oncogenes are derived from the host genome
The search for activated oncogenes: the RAS gene family
Complex genomic rearrangements: the MYC gene family
Proto-oncogene activation by gene amplification
Proto-oncogene activation by chromosomal translocation
Chromosomal translocations in liquid and solid tumors
Chronic myeloid leukemia and the Philadelphia chromosome
Ewing’s sarcoma and the oncogenic activation of a transcription factor
Oncogene discovery in the genomic era: mutations in PIK3CA
Selection of tumor-associated mutations
Multiple modes of proto-oncogene activation
Oncogenes are dominant cancer genes
Germline mutations of RET and MET confer cancer predisposition
Proto-oncogene activation and tumorigenesis
Chapter 3: Tumor Suppressor Genes
What is a tumor suppressor gene?
The discovery of recessive cancer phenotypes
Retinoblastoma and Knudson’s two-hit hypothesis
Chromosomal localization of the retinoblastoma gene
The mapping and cloning of the retinoblastoma gene
Tumor suppressor gene inactivation: the second ‘hit’ and loss of heterozygosity
Recessive genes, dominant traits
APC inactivation in inherited and sporadic colorectal cancers
P53 inactivation: a frequent event in tumorigenesis
Functional inactivation of p53: tumor suppressor genes and oncogenes interact
Germline inheritance of mutant P53: Li Fraumeni syndrome
Cancer predisposition: allelic penetrance, relative risk and odds ratios
Breast cancer susceptibility: BRCA1 and BRCA2
Genetic losses on chromosome 9: CDKN2A
Complexity at CDKN2A: neighboring and overlapping genes
Genetic losses on chromosome 10: PTEN
SMAD4 and the maintenance of stromal architecture
Two distinct genes underlie neurofibromatosis
Multiple endocrine neoplasia type 1
Most tumor suppressor genes are tissue-specific
Modeling cancer syndromes in mice
Tumor suppressor gene inactivation during colorectal tumorigenesis
Inherited tumor suppressor gene mutations: gatekeepers and landscapers
Maintaining the genome: caretakers
Chapter 4: Genetic Instability and Cancer
What is genetic instability?
The majority of cancer cells are aneuploid
Aneuploid cancer cells exhibit chromosome instability
Chromosome instability arises early in colorectal tumorigenesis
Chromosomal instability accelerates clonal evolution
What causes aneuploidy?
Transition from tetraploidy to aneuploidy during tumorigenesis
Multiple forms of genetic instability in cancer
Defects in mismatch repair cause hereditary nonpolyposis colorectal cancer
Mismatch repair-deficient cancers have a distinct spectrum of mutations
Defects in nucleotide excision repair cause xeroderma pigmentosum
NER syndromes: clinical heterogeneity and pleiotropy
DNA repair defects and mutagens define two steps towards genetic instability
Defects in DNA crosslink repair cause Fanconi anemia
A defect in DNA double strand break responses causes ataxia-telangiectasia
Bloom syndrome features hyper-recombination
Aging and cancer: insights from the progeroid syndromes
Overview: genes and genetic instability
Chapter 5: Cancer Gene Pathways
What are cancer gene pathways?
Cellular pathways are defined by protein-protein interactions
Individual biochemical reactions, multistep pathways, and networks
Protein phosphorylation is a common regulatory mechanism
Signals from the cell surface: protein tyrosine kinases
Membrane-associated GTPases: the RAS pathway
Genetic alterations of the RAS pathway in cancer
Membrane-associated lipid phosphorylation: the PI3K/AKT pathway
Genetic alterations of the PI3K/AKT pathway in cancer
Morphogenesis and cancer: the WNT/APC pathway
Inactivation of the WNT/APC pathway in cancers
TGF-b/ SMAD signaling maintains tissue homeostasis
C-MYC is a downstream effector of multiple cancer gene pathways
p53 activation is triggered by damaged or incompletely replicated chromosomes
p53 induces the transcription of genes that suppress cancer phenotypes
The MDM2-p53 feedback loop
The DNA damage signaling network activates interconnected repair pathways
Inactivation of the pathways to apoptosis in cancer
RB and the regulation of the cell cycle
Several cancer gene pathways converge on cell cycle regulators
Many cancer cells are cell cycle checkpoint-deficient
Overview: dysregulation of cancer gene pathways confers selective advantages
Chapter 6: Genetic Alternations in Common Cancers
Cancer genes cause diverse diseases
Cancer incidence and prevalence
Lung cancer
Prostate cancer
Breast cancer
Endometrial cancer
Lymphoma
Bladder cancer
Melanoma of the skin
Ovarian cancer
Cancer of the kidney
Leukemia
Pancreatic cancer
Cancers of the oral cavity and pharynx
Cancer of the uterine cervix
Thyroid cancer
Stomach cancer
Brain tumors
Liver cancer
Chapter 7: Cancer Genetics in the Clinic
The uses of genetic information
Elements of cancer risk: carcinogens and genes
Identifying carriers of germline cancer genes
Altered genes as biomarkers of cancer
Detecting early cancers via gene-based assays
The majority of current anticancer therapies inhibit cell growth
Molecularly targeted therapy: BCR-ABL and imatinib
Clonal evolution of therapeutic resistance
Allele-specific cancer therapy: gefitinib
Antibody-mediated inhibition of receptor tyrosine kinases
Targeting death receptors: TRAIL
Customized cancer therapy
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