• background radiation and oxidative stress
• natural chemicals in food (cooked and uncooked)
• natural chemicals in bodily waste products
• non antrhopomorphic hydrocarbons

• vast majority of DNA damage and mutations are probably endogenous and/or by chance
• nearly 1/3 of our total complement of genes is dedicated to DNA repair

• tumors are clonal in origion and progression requires accumulation of genetic changes
• also influenced by personal and culture behavior superimposed on hereditary susceptibility

Remember, vast majority of cancer is disease of aging

• procarcinogens (not damaging) when metabolized can become excretable metabolites OR an ultimate carcinogene
• carcinogen acts as reactive elctrophile binding to DNA and leading to DNA mutation

• pyrimidine dimer
• ayprimidinic site
• DNA-DNA cross link
• single strand break

The more DNA repair you have, the less likely your repair system can keep up.

• base substitution
  • upon substitution, when DNA is replicated, it will be FIXED into the genome
  • leads to different AA it codes for
• frameshift mutation
  • add or drop anything other than 3 bases, you have shifted the reading frame
  • this leads to the wrong reading of DNA
  • this tends to completely inactivate a gene (if this happens to be a tumor suppressor, you are in trouble)

1. initiation (some genetic/cellular stress)
2. promotion
3. conversion (mainly epigenetic)
4. malignant progression

• additional genetic and cellular stress
• activation of oncogene
• inacivation of tumor suppressor gene
• aneuploidation
• telomerase activation
• imortalization
• genomic instability and mutator phenotype

The final four lead us into conversion

• can be reversible or irreversible
• can be mutagenic or epigenetic
• they all lead to increase proliferation and decreased cell death, causing a phenotypic growth advantage

• up/dys-regulation of transcriptional activity
• gene chromosome abnormality
• further disruption in cell cycle circuitry
• activation/secretion of invasion associated cell surface molecules

• driving cell cycle (cyclin, GF, CDK)
• remove restraint on cell cycle (p53)
• prevent apoptosis (BCL, p53)
• escape senescence (reactivate telomerase)
• block communication

• caretaker genes- affect susceptibility by indirectly suppressing neoplasia
  • mechanism- DNA repair, maintaining genomic stability
  • examples: FA, ATM, BRCA1,2
• gatekeeper genes- restain cell growth, so directly suppress neoplasia
  • mechanism
    • increase in apoptosis (ex: BCL-2)
    • induce senescence of terminal differentiation
    • inhibit cell cycle (p53, p21, RB1)

1. normal cell loses APC (mutation at 5q) resulting in increase cell grwoth
2. now DNA loses a methyl group, causing an early adenoma
3. mutation on K-RAS gene (12q), an oncogene), leads to middle adenoma
4. loss of DCC on chromosome 18 causes late adenoma
5. mutation of p53 at chromosome 17p (loss) leads to carcinoma
6. expression of metalloproteinase leads to metastasis