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 SuppressorGenes 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
This concise guidebook 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.
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 concise guidebook consolidates the main concepts of the cancer gene theory, and provides a framework for understanding the genetic basis of cancer. The book is focused on the most highly representative genes that underlie the most common cancers and highlights new frontiers in gene-based diagnosis and therapy. 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.