The Biology of Cancer

Human Cancer Risk Factors

Viruses

Varieties of Viruses Implicated in Raising the Risk of Cancer

Tumor Virus Theory

Genetic/Cytogenetic Factors

Methods of Studying Human Cancer

Chromosomal Disorders

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Viruses

• Cervical Cancer
  • Epstein-Barr
  • Human Papilloma Virus (genital warts)
• Pavosi's sarcoma (?)
• Liver Cancer
• Hepatitus B, contains no oncogene: may not be direct cuase. Hepatitus B does cause sclerosis, which increases proliferation in liver cells and may increase the risk of mutation simply by raising the number of cell divisions. Hepatitis C, an RNA virus, may also be associated with liver cancer.

Human T-Cell Leukemia is associated with the RNA virus (retrovirus) HTLV1. The genome it carries in exogenous. It is a C-type virus (with an envelope and centric nucleus). If this virus infects a young adult, it increases the risk of tumors 20-30 years later. There is a 1% chance of developing very virulent lymphoma.

Evidence for the Association between HTLV1 and Human T-Cell Leukemia

• Serum from leukemia contains HTLV1 antibodies
• CD4+ (Human T-Cell) Leukemia are all found in patients infected with HTLV1
• HTLV1 can infect and immortalize T Cells in vitro
• Viral integration is random, but only Adult T-Cell Leukemia shows integration of this virus: Other leukemias do not

How could this virus cause cancer? The HTLV1 genome contains a fourth gene, X, which codes for two proteins, Tax and Rex.

• Tax: Master switch. Turns on viral LTR, enhancer, and promoter
  • Tax can also stimulate the host IL2, IL1, and GMCSF (granulocyte macrophage colony stimulating factor, or something like that). This ability is thought to be involved inthe transformation process.
• Rex: Determines the level of mRNA produced

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• Familial
  • Low frequency
  • Occurs early in life
  • Occurs in multiple sites in the same organ
• Sporadic
  • Higher frequency (accounts for a higher percentage of all observed cancers)
  • Occurs later in life
  • Occurs at single sites

Knudse, a genetic epidemologist in Houston, showed in 1971 that All hereditary cancers have two steps. Each tumor is caused by two mutations. These mutations can be:

• pre-zygotic, genetic traits passed down from the parents
• post-zygotic, mutations which occur after the organism is formed

• Inbred strains of mice can have 100% or 0% incidence of any given cancer, indicating that susceptibility or resistance may be genetic
• Human cancer epidemology shows some familial aggregation
  • ~15% of human cancers may be familial
  • However, this may also be due to environmental factors
  • With this in mind, probably about 5% of human cancers are due to a genetic trait

• Twin Studies
  • Compare identical and fraternal twins to the rest of the population
  • Environmental factors are a problem
  • In addition, there are a limited number of cases so coincedental fluctuation can greatly skew the results
  • In theory, if the cancer is genetically transferred, both twins will show early incidence of tumors
• Families
  • Li-Frameni Syndrome leads to multiple tumors in many organs
    • The loss of the p53 gene has been implicated in the familial incidence of Li-Frameni syndrome
• Racial Variation
  • Usually environmental rather than genetic (i.e. food contamination or environmental toxin)
  • Nasopharygenal cancer
    • Endemic to China
    • MHC gene has been implicated
  • Leukemia is more common in the Jewish population
  • Skin cancer less common in darker people
• Following Progeny/Mendelian Inheritance
  • Polygenic
    • Most common cancers are polygenic
    • Lung, colon, prostate, endometrial
    • A family can have 2-4x higher incidence of these cancers than normal
    • Mostly due to environmental factors
  • Single gene which increases the risk for cancer
    • Truly familial
    • For example, retinoblastoma, basal cell carcinoma, polyposis coli, thyroid medullary
  • Single gene which increases the risk for preneoplasia
    • Excess tissue growth
      • Neurofibromastosis: Increase in peripheral nerves. Schwann cells increase their proliferation, and there is a 10% chance of developing sarcoma
    • DNA repair defective, for example, Xeroderma Pigmentosa
      • Autosomal recessive
      • acute sensitivity to light
      • dry scaly skin and dilated blood vessels
      • High risk for skin cancer: basal cell/squamous cell
      • No UV repair system exists in these hosts
    • Metabolic disorder, for instance, albinos
      • Cannot synthesize melanin
      • abnormal tyrosine metabolism
      • Autosomal recessive
    • Immue deficiency
      • Missing T-cells will increase risk for leukemia/lymphoma
  • Cytogenetic changes
• Cytogenetic Alterations
• Molecular Studies
• Human Genome Project

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• Down's Syndrome is associated with trisomy 21. It carries a high risk of leukemia (20-50% higher than the general population)
• Kleinfeller's Syndrome describes males with an extra X chromosome. Their risk for breast cancer is similar to that of a female.
• Bloom's Syndrome has a higher incidence in people of Jewish, Polish, and Ukraine descent. It is associated with the formation of quadroradial chromosomes, and with a higher risk of skin cancer and leukemia. Symptoms include dwarfism and increased light sensitivity.
• Chronic Myologenous Leukemia was discovered in 1960 by Nowell and Hungerford at the Phlidelphia Cancer Institute. It was discovered that the cause was a nonrandom deletion of the long arm of the Philadelphia Chromosome (22q). This results from recombination with the long arm of the #9 chromosome (9q).

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