Cancer Genetics

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Cancer Genetics
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Introduction

• Cancer uncontrolled proliferation of cells
  somewhere in the body
• Loss of control of the cell cycle
• Cancer is genetic, but not inherited

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Definitions

• Tumor (aka-neoplasm)-growing mass of abnormal
  cells
• Benign-single clustered mass of neoplastic cells
• Malignant-cells invade surrounding tissue
• Metastasis-spread of cancer cells/formation of
  secondary tumors at other sites

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Types of Cancers

• Carcinoma-epithelial tissue cancer
• Ie. Breast, skin, colon
• Sarcoma-connective tissue cancer
• Ie. Muscle, bone
• Leukemia-cancer of blood forming tissues
• Glioma, neuroblastoma-nervous tissue cancer

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Cells Dont All Divide at the Same Rate

• No cell division-neurons, skeletal muscle cells
• Slow cell division-liver cells divide once or
  twice a year
• Rapid cell division-gut epithelial cells divide
  more than twice per day

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Cells Division Rate Varies With External
Environment

• Blood loss-proliferation of blood cell precursors
  (aka blood stem cells)
• Acute liver damage-liver cells can regenerate
• Wounds-cells in neighborhood of wound are
  stimulated to divide to repair lesion

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Contact Inhibition

• Aka- density dependent inhibition
• Normally, when cells are touched on all sides by
  other cells, they stop dividing
• Cancer cells dont obey the rules
• Begin to invade tissue because they divide faster
  than other cells

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Figure 12.16 Density-dependent inhibition of
cell division
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How Cancer Begins

• Scientists have noticed for centuries the
  correlation between
• carcinogenesis-generation of cancer
• and mutagenesis-change in DNA sequence

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Carcinogens

• Chemicals that induce cancer
• Act directly or are activated metabolically
• I.e. Tobacco smoke

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Mutagens

• Substances that induce mutations in DNA
• I.e., ionizing radiation, x-rays
• Not all mutagens are carcinogens

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Molecular Genetics of Cancer

• Cancer is disruption of cell growth controls
• Cells remain in G1 until chemicals signal them to
  go to the next stage
• depends on
• growth factors from outside the cell (first
  messengers)
• transcription factors from within

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Proto-oncogenes

• products of these genes stimulate an increase in
  cell number
• Are growth stimulators
• I.e. a GO signal
• or a cars accelerator
• Mutation causes gene to become an oncogene, or
  tumor gene
• Result is an inappropriate rate of mitosis, too
  fast
• accelerator stuck

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Proto-oncogenes

• active where and when a high rate of cell
  division is necessary
• I.e. Wound healing, growing embryos
• When mutated, products are over-expressed
• Become oncogenes, or cancer-causing genes

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Figure 19.13 Genetic changes that can turn
proto-ocogenes into oncogenes
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Tumor Suppressor Genes

• Genes whose products inhibit cell growth
• I.e. STOP signal
• Or like a cars brake
• Some commit the cell to apoptosis
• Mutation of these genes causes less cell death

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p53-a tumor suppressor

• first described as protein of 53,000 MW
• Codes for a transcription factor, or a genes on
  switch
• Gene products job is to delay the cell cycle at
  G1
• Allows cell to repair DNA damage, stop dividing,
  or undergo apoptosis
• No delay-cell divides despite DNA
  damage-replicates these mistakes
• About 50 of cancers involve p53 mutations

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How Does a Cell Decide to Divide?

• Cell signal transduction
• 1st messenger signals cell
• 2nd messenger relays message to nucleus in a
  series of step
• Like a bucket brigade
• Current model has 10 steps
• Each step is controlled by a gene

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Cancer not caused by a single mutation

• Cancer rate increases with age-why?
• The longer you are alive, the more you have
  exposed to mutagens
• Current model-cells require between 4-9 mutations
  in the cell signaling pathway of the SAME cell to
  become a cancer cell
• Progressive loss of control of cell cycle in that
  cell
• Mitosis rate in that cell increases
• Its descendents increase faster than cells around
  it

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Figure 19.14 Signaling pathways that regulate
cell growth (Layer 1)
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Figure 19.14 Signaling pathways that regulate
cell growth (Layer 2)
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Figure 19.14 Signaling pathways that regulate
cell growth (Layer 3)
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The picture becomes more clear.

• The steps are products of proto-oncogenes and
  tumor suppressor genes
• Ie. normal cell growth regulators
• Cancer is the result of damage to the DNA in the
  genes that control the cell cycle
• Therefore, all cancer is genetic

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Some cancers run in families

• Recall that in order for changes in genes to be
  inherited, they must occur in the germ line
• These are usually somatic cell mutations which
  arent inherited
• If in the germ line, however, single mutations
  can be inherited
• Ie. would be born with a predisposition to
  cancer
• Inherit one or two already mutated cell cycle
  genes
• Colon cancer runs in families
• BRCA1, BRCA2 genes in breast cancer

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Figure 19.15 A multi-step model for the
development of colorectal cancer
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Cancer and age

• The above mutations would happen over time and
  accumulate
• Perhaps individual above was born with already
  mutated APC gene
• Forms polyps more readily than general population
• Other random mutations happen over time in cells
  of polyp
• Cancer eventually develops
• Can try to control exposure to mutagens