Cancer: a genetic disease of inherited and somatic mutations

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Cancer a genetic disease of inherited and
somatic mutations

• Gene mutations and/or genetic instability are
  involved in many cancers.
• Viruses and environmental agents implicated in
  cancer are believed to act by causing mutations.
• Mutated gene include those classified as
  gatekeepers (oncogenes and tumor suppressor
  genes) or caretakers (encoding proteins
  involved in DNA repair and chromosome
  segregation).
• For the most part, these genes confer
  predisposition or susceptibility to cancer.

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Cancer and the Cell Cycle

• Understanding the cell cycle is key to
  understanding cancer.
• Misregulation of the cell cycle is a frequent
  event in tumorigenesis.
• The cell cycle is controlled at several key
  checkpoints G1/S and G2/M.

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Familial Retinoblastoma and the Two-Hit Hypothesis

• A clear-cut case of inherited prediposition due
  to a single gene is retinoblastoma, providing
  evidence for a two-hit model in which both
  alleles must be mutated to express cancer.
• Familial retinoblastoma inheritance of single
  mutant allele and spontaneous somatic mutation of
  other
• Sporadic retinoblastoma inheritance of two
  normal alleles and sequential spontaneous somatic
  mutation of both

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Most cancers require sequential somatic mutation
of several genes

• A well-studied example is colon cancer, studied
  by Vogelstein and Kinzler.
• Several different genes, including p53, are
  mutated in a sequential order.
• These basic findings of Vogelstein and Kinzler
  have revolutionized clinical diagnosis and
  prevention of death.

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Genomic instabilities can activate cancer

• Somatic chromosome translocations can juxtapose
  sequences, leading to activation of of tumor
  promoters.
• Failure to monitor DNA change can lead to somatic
  mutation and cancer, such as hereditary
  nonpolyposis colon cancer.

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Gatekeeper genes

• The gatekeeper gene monitor cell proliferation
  and death. They include
• oncogenes which are cell growth promoters,
  where dominant mutations lead to uncontrolled
  growth, and
• tumor suppressor genes which are negative
  regulators of cell growth, where recessive
  mutation can lead to uncontrolled cell growth
  (e.g., p53).

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Caretaker genes

• The caretaker genes include genes that regulate
  DNA repair and chromosome segregation in mitosis.
  Mutation of of these genes can cause abnormal
  gatekeeper function because of mutation or
  abnormal gene content. The caretaker genes
  include
• DNA repair genes, whose mutations lead to genetic
  instability (more mutations), and
• genes that regulate chromosome segregation, whose
  mutations lead to abnormal chromosome content, or
  chromosomal instability.