The Genetics of Cancer

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The Genetics of Cancer
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Cancer in the media
Newspapers, magazines, radio, and television are
reporting discoveries and breakthroughs
attributing one form of cancer or another to a
specific gene. Cancer of the breast, colon,
prostate, and many other sites in the body are
being connected to specific genes... But the
meaning of this isn't always clear.

• What does it mean for you if your mother has or
  had breast cancer... or an aunt and two cousins
  have colon cancer?
• What does it mean for your children if you've
  been diagnosed with cancer of the endocrine
  glands or some other organ?

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cancer is a disease of the cell cycle
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Types of genes which may mutate to cause cancer

• Tumour suppressor genes
• oncogenes
• DNA repair genes
• telomerase
• p53

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The environment

• Some environmental agents associated with cancer
  are
• Viruses
• Tobacco smoke
• Food
• Radiation
• Chemicals
• Pollution

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Viruses
Virusesmostly in the form of DNA viruseshave
been causally linked to cancer.

• human papillomavirusesprimarily types 16 and 18,
  which are sexually transmittedhave been linked
  to cervical cancer
• more than 25 other types of papillomaviruses have
  been linked to cancer as well
• hepatitis B and Clinked to cancer of the liver
• human immunodeficiency virus (HIV)linked to
  Kaposi's sarcoma and lymphoma
• retroviruseslinked to cancers in animals other
  than humans

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Tobacco smoke

• is associated with 50 to 60 of all cancer
  deaths
• is causally linked to cancers of the lung, upper
  respiratory tract, oesophagus, bladder, pancreas
• is probably a cause of cancer of the stomach,
  liver, kidneys, colon, and rectum

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Food

• is connected to 50 to 60 of cancer deaths
• is causally linked to cancers of the lung, upper
  respiratory tract, oesophagus, bladder, pancreas
• is probably a cause of cancers of the stomach,
  liver, kidneys, colon, and rectum

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Radiation

• UVB from the sun can damage DNA and is associated
  with more than 90 of skin cancers, including
  melanomas
• radon has been associated with lung cancer among
  those who work in mines general levels of radon
  have not posed a significant cancer threat
• electric and magnetic fields from power lines and
  household appliances have not been demonstrated
  contributors to the incidence of cancer or
  leukaemia
• radio frequency electromagnetic radiation from
  mobile phones or microwave ovens has not been
  linked to cancer.
• nuclear radiation is of sufficient energy to
  ionise molecules and is therefore carcinogenic.

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Chemicals
Chemicals, many of which have been historically
linked to the workplace, have been successfully
limited through public health efforts, because
they have been associated with a variety of
cancers. Examples of common chemicals that fall
in this category are

• benzene (myelogenous leukaemia)
• arsenic containing pesticides (lung cancer)
• polychlorinated biphenyls (liver and skin
  cancers)
• mineral oils (skin cancer)
• mineral fibres (lung cancer and mesothelioma)

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Pollution
Pollution has been difficult to document as a
contributor to human cancer. However, long-term
exposure to high levels of air pollution may
increase lung cancer risk by as much as 25.
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Cancer terminology

• Classification by tissue type
• carcinomaepithelial cell90 of all
  tumoursderived from ectoderm (mostly) or
  endoderm (some)
• sarcomaconnective tissue2 of all
  tumoursderived from mesoderm
• leukaemiacirculatory or lymphatic8 of all
  tumoursderived from mesoderm

• Classification by the type of cells
• Adenomatous cellsductal or glandular cells
• Squamous cellsflat cells
• Myeloidblood cell
• Lymphoidlymphocytes or macrophages

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Cancer terminology

• Classification by the site of origin of the
  tumour
• Breast carcinoma of ductal, medullary,
  papillary, etc. cells
• Lung small cell, bronchioloalveolar, squamous,
  large cell carcinomas
• Bone osteosarcoma, Ewing's sarcoma
• Eye retinoblastoma
• Lip, tongue, mouth, nasal cavity squamous cell
  carcinoma
• Lymphocytes acute lymphocytic leukaemia, chronic
  lymphocytic leukaemia, Hodgkin's lymphoma
• Ovary adenocarcinoma, choriocarcinoma, teratoma,
  Brenner tumour
• Testis seminoma, teratocarcinoma,

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Cancer terminology

• Benign tumours
• are generally slow growing and enclosed in a
  fibrous capsule
• are relatively innocuous, although their location
  can make them serious (such as a tumour located
  in the brain)
• are not considered cancerous (that is, they are
  not malignant)
• are given names that usually end in "oma"
  (although a melanoma is a malignant skin cancer)
• Malignant tumours
• proliferate rapidly, invading neighbouring
  tissues
• can metastasise, or spread, to other sites of the
  body
• are named using the conventions of tissue, cell
  type, and origin

e.g. A tumour of the bone is an osteoma if benign
and an osteosarcoma if malignant
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Tumour suppressor genes

• The genes normal function is to regulate cell
  division. Both alleles need to be mutated or
  removed in order to lose the gene activity.
• The first mutation may be inherited or somatic.
• The second mutation will often be a gross event
  leading to loss of heterozygosity in the
  surrounding area.

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Knudsens two hit hypothesis
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retinoblastoma
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retinoblastoma

• Retinoblastoma (RB) is a malignant tumor of the
  developing retina that occurs in children,
  usually before the age of five years.
• All forms of retinoblastoma represent a mutation
  in the gene RB1 located in in the region
  13q14.1-q14.2.
• The gene is about 180 kb in length with 27 exons
  that code for a transcript of only 4.7 kb.
• individual mutations are heterogeneous 20 are
  deletions larger than 1kb 30 are small
  deletions or insertions 45 are point mutations.
  
• mutations have been found in 25 of the 27 coding
  exons and in promoter elements.
• Genotype-phenotype correlationmost mutant
  RB1-alleles show premature termination codons and
  are associated with almost complete penetrance
  (gt95) and high expressivity (more than 6
  individual retinoblastoma foci per individual
  and, therefore, most often involvement of both
  eyes)some rare mutant alleles that code for
  proteins with retention of parts of the functions
  of the wild-type protein or that result in
  diminished amounts of wild-type transcript are
  associated with incomplete penetrance (lt75) and
  low expressivity (mean of less than 2 tumor foci)

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RB1

• Is regulated by phosphorylation by Cdk2
• Hypophosphorylated form binds and sequesters E2F
  (and viral proteins such as E7 from human
  papilloma virus-16)
• It also interacts directly with the product of
  the ABL gene and participates in several
  regulatory and feed back loops even involving its
  own transcription.

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Breast Cancer
Why do so many of my relatives have breast
cancer...is this just plain bad luck or what?
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breast cancer
Within the general population, there is an 11
chance that any woman will develop breast cancer
over her lifetime. For any one individual, this
risk may be increased or decreased by a variety
of factors

• her age,
• family history,
• age at which she began menstruating,
• whether she has given birth and her age at the
  time of the first birth, and
• whether or not a breast biopsy was performed in
  the past.

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breast cancer
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But its more complicated than that!
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oncogenes

• Cellular oncogene c-onc
• Viral oncogene v-onc
• Proto-oncogene, activated by mutation to c-onc

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Proto-oncogene activation
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Types of proto-oncogene

• Growth factore.g. SIS oncogene (PDGF)

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Types of proto-oncogene

• Growth factor receptore.g. tyrosine kinase
  receptors

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Types of proto-oncogene

• G proteinse.g. ras

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Types of proto-oncogene

• Nuclear transcription factorse.g. MYC

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(No Transcript)
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p53

• suppresses progression through the cell cycle in
  response to DNA damage
• initiates apoptosis if the damage to the cell is
  severe
• acts as a tumour suppressor
• is a transcription factor and once activated, it
  represses transcription of one set of genes
  (several of which are involved in stimulating
  cell growth) while stimulating expression of
  other genes involved in cell cycle control

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Transformation is a multistep process
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Transformation is a multistep process
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Colorectal Cancer

• 11 of cancer-related deaths
• Tumor progression may take 10-35 years
• Adenomatous polyp develops into carcinoma

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Chromosome changes in colorectal cancer
Cancer karyotype
Stable karyotype
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reading

• URLs
• http//www.infobiogen.fr/services/chromcancer/Kpro
  nes/RbKprID10031.html
• http//cgap.nci.nih.gov/
• http//www.intouchlive.com/home/frames.htm?http//
  www.intouchlive.com/cancergenetics/3
• http//bioinformatics.weizmann.ac.il/hotmolecbase/
  entries/p53.htm
• Books
• Concepts of Genetics, Klug and Cummings, chapter
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• Molecular Biology of the Cell