Cancer Genetics

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Cancer Genetics

• From Chapter 18
• Human Genetics Concepts and Applications
• 6th edition by Ricki Lewis

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What is cancer?

• From Greek karkinos for crab
• A group of diseases caused by loss of cell cycle
  control
• Characterized by abnormal, uncontrolled cell
  growth

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What causes cancer?

• Begins with 1 or more mutations in a single
  somatic cell (a.k.a. the bad apple)
• Mutation allows cell to divide when it normally
  would not
• Further cell division produces more abnormal
  cells
• Somatic cell mutations may be due to
• Carcinogens
• Inheritance
• Natural mistakes in replication process
• Genetic predisposition to mutation/lack of
  mutational repair

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Pre-cancer and cancer progression

• Tumor growth caused by cell escaping normal
  cell cycle control
• Benign tumor grows in one place
• Malignant (cancerous) spreading tumor
• Local invasion by crab-like arms
• Transportation through bloodstream
• Metastisis (not standing still) process of
  spreading of abnormal, malignant cells

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World view of cancer

• Environment-only view of cancer lead to War on
  Cancer and legislation in 1971
• Targeting radiation, viruses, chemicals
• Fueled by lack of understanding of biology of
  disease
• Genes first implicated in cancer in 1976

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In US Approx 1,500,000 new cases of
cancer/year Approx 500,000 deaths/year
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Killer cancer
Women
Men
Lung
Lung
Breast
Prostate
Colon/rectum
Colon/rectum
Of the 200 types of cancers, 85 are CARCINOMAS
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Mutations and cancer

• Mutations can occur
• In somatic cells sporadic cancer only
  affecting the individual
• In germline cells mutations that are
  inherited
• Accounts for only 10 of cancers
• usually require second somatic mutation

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Germline versus sporadic cancer
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Control of the cell cycle
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Telomeres affect the cell cycle
When telomerase is absent, telomeres are not
added. Lack of telomeres signals cessation of
cell division.
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Telomeres affect the cell cycle
Telomerase is the protein and enzyme complex that
adds telomere sequences to the ends of
chromosomes. Presence of telomerase and
telomeres allows cells to pass a cell cycle
checkpoint and divide.
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Cancer cells look act different

• Divide continually (given space and nutrients)
• Heritable mutations cells with mutations have
  daughter cells which inherit the same mutations.
• Transplantable
• Dedifferentiated cells lose their specialized
  identity
• Different appearance reflects dedifferentiation
• Lack contact inhibition will divide in a crowd
  of cells and pile on top of each other
• Induce angiogenesis (local blood vessel
  formation)
• Increased mutation rate
• Invasive squeeze into any space available
• Metastasize cells move to new location in the
  body

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Types of cancer-causing genes
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Oncogenes

• Proto-oncogenes are normal versions of genes
  which promote cell division.
• Expression at the wrong time or in the wrong cell
  type leads to cell division and cancer.
• Proto-oncogenes are called oncogenes in their
  mutated form.
• One copy of an oncogenic mutation is sufficient
  to promote cell division.

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Oncogenes overexpression of a normal function

• Viruses integrated next to a proto-oncogene can
  cause transcription when the virus is
  transcribed.
• Moving a proto-oncogene to a new location can
  separate the coding region from regulatory
  regions of the gene leading to incorrect
  expression.
• Moving a proto-oncogene next to a highly
  transcribed gene can lead to erroneous
  transcription of the proto-oncogene.

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Chronic Myelogenous Leukemia

• Invariably fatal
• The Philadelphia Chromosome
• Reciprocal Translocation
• long arm of HAS 22 small part of HSA 9
• 2 chromosomal changes
• Translocation causes oncogene activation

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CML

• HSA 9 gene Abelson oncogene (abl)
• HSA 22 gene breakpoint cluster region (bcr)
• bcr-abl fusion gene encodes a form of tyrosine
  kinase
• Tyrosine kinase is normal produce to abl
• bcr-abl fusion version active for too long
• Cell divides for too long
• Gleevec- drug that binds ATP-binding pocket of
  tyrosine kinase, preventing the stimulation of
  cell division

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Burkitt's Lymphoma

• Common in Africa
• Viral induced tumor of the immune system (B cell
  genes)
• Usually associated with a reciprocal
  translocation between chromosomes 8 and 14.
• Evidence for a oncogene (c-myc)

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Tumor suppressor genes

• Cancer can be caused by loss of genes that
  inhibit cell division.
• Tumor suppressor genes normally stop a cell from
  dividing.
• Mutations of both copies of a tumor suppressor
  gene is usually required to allow cell division.

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Retinoblastoma

• A rare childhood eye cancer
• Alfred Knudson, 1971 examined cases of
  retinoblastoma in Houston from 1944-69 and
  determined
• One eye or two with tumor
• Age of diagnosis
• Relatives with retinoblastoma
• Number of tumors per eye
• Observed that 50 of children of an affected
  parent were affected.
• Boys and girls were equally frequently affected.
• Children with bilateral (both eyes) tumors were
  diagnosed earlier.

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Knudsons two hit hypothesis

• Two mutations are required, one in each copy of
  the RB gene (recessive expression)
• For sporadic cases, retinoblastoma is a result of
  two somatic mutations
• Mostly single-eye
• For familial cases, retinoblastoma is inherited
  as an autosomal recessive mutation followed by a
  somatic mutation in the normal allele.
• Can be both eyes, single eye, or none (skips
  generation)
• Gene isolated to HAS 13q through deletion studies
• 928-aa long protein encodes protein that bind txp
  factors
• Results in halting of cell cycle at G1
• Mutant or missing RB gene no hold on txp factor
  cell division

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p53 coordinates cell cycle regulation

• p53 acts as a cell cycle protein which determines
  if a cell has repaired DNA damage. If damage
  cannot be repaired, p53 can induce apoptosis.
• More that 50 of human cancers involve an
  abnormal p53 gene
• Many different types of mutations in p53 gene
• e.g. colon, breast, bladder, lung, liver, blood,
  brain, esophagus, skin
• Rare inherited mutations in the p53 gene cause a
  disease called Li-Fraumeni syndrome in which
  family members have many different types of
  cancer at early ages.

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BRCA1, a breast cancer susceptibility gene

• BRCA1 breast cancer predisposition gene 1
• tumor suppressor gene
• Within families a mutation in BRCA1 leads to
  breast cancer susceptibility, inherited as a
  dominant trait.
• One mutation in the BRCA1 gene is inherited.
• Tumors in people acquire a second mutation in the
  normal allele of BRCA1.
• Lack of any functional BRCA1 leads to cancer
  cells.
• At the level of the cell, BRCA1 acts in a
  recessive manner.

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Complexities in genetic counseling for familial
breast cancer

• Many mutations are known but not all are
  associated with disease
• Some are polymorphisms
• Individuals with inherited predisposition and
  individuals with sporadic cancer can be found
  within the same family.
• BRCA1 and BRCA2 are not fully penetrant.
  Occasionally individuals with a mutation do not
  develop cancer.
• Risk associated with BRCA1 or BRCA2 mutations
  depends on interaction with other genes
  environmental exposures

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Multiple genes contribute to cancer progression
Multiple genetic changes in astrocytes, nerve
support cells, cause in cancer growth.
Astrocytomasa are most common type of brain
tumors Grow VERY quickly
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Colon cancer results from genetic alterations in
multiple genes
Inherited mutations in the APC gene dramatically
increase risk of colon cancer 5 of cases are
inherited 1/5,000 in US have precancerous colon
polyps
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Environment impacts cancer

• Exposure to carcinogens
• Carcinogens in tobacco smoke are correlated with
  lung cancer incidence.
• Exposure to radiation
• Burns from overexposure to sunlight can cause
  skin cancer.
• Variation in diet
• Fatty diets are correlated with increased
  estrogen and increased breast cancer.

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Cancer can progress slowly over years.
but can also progress very rapidly!
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The Skin Cancer Epidemic

• The most common form of human cancer
• 1 in 5 lifetime risk.
• Tenfold increase since 1967!!!
• Be smart, protect yourself!
• like many cancers, your actions can prevent or
  limit your chances of having this disease

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Cancer treatments for breast cancer
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Methods for evaluating environmental impacts of
cancer

• Population studies compare incidence of a
  cancer trait among different populations.
• Case-control studies compare individuals with
  cancer to healthy individuals matched for
  characteristics such as age, sex, and ethnic
  background.
• Prospective studies follow the outcome of
  individuals placed in two or more groups who have
  different treatments, conditions, or procedures.

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Cruciferous vegetables can lower cancer risk
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Questions about specific cancer types? Go to
Online Medelian Inheritance in Man
website http//www.ncbi.nlm.nih.gov/omim/