The Genetics of Cancer

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The Genetics of Cancer Presenters Patrick
Day Rachael Hanks Leila Shirazi
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History of Cancer

• Cancer has been documented as early as 3000 B.C.
• Recorded treatments of cancer since 1600 B.C.
• Egyptians would burn or cut off cancerous tumors,
  also they would mix pig brains and freshly ground
  dates and insert into the urinary tract for some
  internal cancers
• By 300 B.C Hippocrates had identified several
  different types of cancer
• Cancer effects about 1 out of every 3 people

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Findings of Cancer

• In the 1980s-1990s researchers identified parts
  of the genome that only infected individuals
  shared, such as chromosomal aberration or a
  unique DNA sequence. The research continued on
  specific genes thats could effect cell cycle
  control. This led to the discovery of more then
  100 oncogenes, and more then 30 tumor suppressing
  genes.

• Oncogenes- cause cancer when they are
  inappropriately activated
• Tumor suppressing genes- deletion or inactivation
  of these genes causes cancer.

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Function Of Cancer Genes Discovered

• Dutch researcher Sebastian Nijman has discovered
  new genes which are involved in the development
  of cancer. The results of his research have led
  to a new treatment for patients with an inherited
  form of cancer, cylindromatosis.
  (www.sciencedaily.com)
• Cylindromatosis- Patients with the very rare
  genetic condition cylindromatosis develop a lot
  of benign tumours on the skin. These tumours
  mainly occur on the head where they can cause
  serious malformations.

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Difference Between Cancer cells and Regular cells

• Cancer cells can divide infinitely if provided
  enough nutrients and space
• Cancer cells can produce telomeres
• Cancer cells look much different then a normal
  cell
• Cancer cells can metastasize (Spread)
• Induce local blood vessel formation
• Increased mutation rate

• Normal cells divide until the telomeres on the
  cell run out
• Normal cells do not divide as often as cancer
  cells
• Cell division is controlled
• Adhere to the surroundings of the other cells
  (Takes the same shape as cells around it)
• Plasma membrane has less fluid compared to a
  cancer cell

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Diagram of Cancer cells V.S.Normal cells
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How Cancer cells Form

• Cancer cells are formed when a normal cell looses
  its ability to control its division rate
• Cancer can form from environmental triggers
  Smoking, drinking, stress
• Mutations in cells can cause them to become
  cancerous
• Cancer cells squeeze into the blood stream which
  allow them to travel to other parts of the body
• A loss of balance in tissue cells that can divide
  continually or frequently
• Cancer cells could come from stem cells or
  regular cells that have gone through a series of
  mutations

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Other Causes of Cancer

• Dedifferentiation reverses specialization
• Mutations in a differentiated cell could
  reactivate latent stemness genes, giving the
  cell greater capacity to divide while causing it
  to lose some of its specialization.

• To much repair may trigger tumor formation
• If the epitheluim is occasionally damaged,
  resting stem cells can become activated and
  divide to fill the tissue. If the injury is
  severe, the present activation of stem cells to
  renew the tissue can veer out of control, causing
  an abnormal growth

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DNA Microarrays

• Some cancers look the same as normal cells under
  a microscope, with the use of DNA microarray
  analysis, we have been able to refine and even
  individualize cancer diagnosis and treatment.
• The vertical columns of squares represent tumor
  samples and the horizontal rows compare the
  activities of particular genes- The red tone
  indicates higher-then-normal expression and the
  blue indicates lower-then-normal expression.

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Germline V.S. Sporadic Cancer

• Germline
• In germline cancer, every cell has one gene
  variant that increases the chance of a person
  getting cancer. This type of predisposition is
  known as a Mendelian trait.
• This is a cancer that is passed through
  generations of people and is hard to avoid

• Sporadic
• Sporadic cancer forms when a dominate mutation
  occurs in a cell, this is caused by environmental
  triggers such as exposure to radiation or a
  chemical, can cause the somatic mutations that
  cause cancer.
• This cancer is strictly caused by environmental
  factors and can be avoided

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Causes of Tumors

• Angiogenesis nurtures a tumor
• Cells starved for oxygen deep within a tumor
  secrete vascular endothelial growth factor, which
  stimulates nearby capillaries to extend branches
  towards the tumor helping it to grow.

• Shifting the balance in a tissue towards cells
  that divide
• If a mutation renders a differentiated cell able
  to divide to yield other cells that frequently
  divide, then over time these cells may take over,
  forming an abnormal growth

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Cancer Stem cells

• A cancer stem cell can divide to self-renew and
  give rise to a cancer cell, which in turn can
  also spawn abnormal daughter cells.
• Upsetting the balance of stem and progenitor to
  differentiated cells can cause cancer as excess,
  fast dividing cells accumulate.
• The cancer causing mutations can occur in the
  cancer stem cell- in this case, the early
  progenitor cells form the tumor which may also
  spawn abnormal daughter cells.

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Genes Associated With Cancer

• Oncogenes- (recessive) activate improper cell
  division which leads to cancer. (proto-oncogenes
  are normal and control cell cycles.)
• Tumor suppressors- (dominant) normally prevent
  cancer, but can mutate so that part of a gene is
  missing, thereby eliminating its function and
  causing cancer.
• DNA repair genes- normally repair damaged DNA.
  Faulty DNA allows mutations to build up and
  mutant cells to divide.

The bright blue enlarged cells are carrying
oncogenes.
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Proto-Oncogenes and Oncogenes

• Proto-Oncogenes are active when high cell
  division rates are necessary (like in wounds).
• Oncogenes are point mutations of proto-oncogenes,
  activated at non-wound sites.
• Rapid cell division in undamaged tissue leads to
  cancerous growths (also known as tumors).

A single base change in a proto-oncogene causes
bladder cancer.
The oncogene RET alters growth factors or growth
factor receptors and can lead to Thyroid cancer.
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Transformations of Gene Expressions

• Proto-oncogenes can become oncogenes when placed
  next to virus-infected cells.
• When a chromosome is inverted or translocated,
  proto-oncogenes can turn on and become
  oncogenes if they are moved near very active
  genes.
• The immune system can contribute to
  overexpression of oncogenes by producing an
  excess of antibodies to accommodate oncogenes.

Burkitt lymphoma is caused when proto-oncogenes
are activated along with antibody genes.
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Fusion Proteins

• When proto-oncogenes are read together as a pair,
  the result is a double gene product, or a fusion
  protein.
• Fusion proteins can take control of cell
  division. Rapid cell division can cause cancer.
• Fusion proteins are most commonly associated with
  cancers of the blood, including leukemia.
• Pieces of chromosomes that are randomly
  translocated to others during cell division can
  lead to fusion proteins, and in turn, to various
  cancers.

Fusion proteins can cause childhood cancers of
the blood such as leukemia.
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Excessive Receptor Signals and Her-2/neu Breast
Cancer

• 25 of women with breast cancer have 1-2 million
  copies of an oncogene producer (a protein) called
  Her-2/neu. Normal women have 20,000-100,000
  copies.
• These proteins bind to tyrosine kinase receptors
  which, together, send too many signals to tell
  cells to divide.
• A drug called Herceptin can help by stopping some
  of the receptors from sending out too many
  signals for cell division.

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Tumor Suppressors

• A tumor suppressor can mutate into a gene that
  causes cancer. The mutated gene has usually had
  some kind of deletion which removes part or some
  of its normal functions.

Wilms tumor is the result of a mutated tumor
suppressor. In this form of cancer, a childs
kidney cells divide at the same rate as would an
embryos, forming a tumor.
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Retinblastoma (RB)

• Retinoblastoma or (RB) is a rare childhood eye
  cancer.
• Most RB is the result of a partial deletion on
  Chromosome 13.
• In 1987, researchers found the RB gene and have
  linked it to other cancers such as breast, lung,
  and prostate cancer.

RB is a childhood eye cancer that results in one
or both of the eyes developing an average of
three tumors.
On the left is a normal cell with no Chromosome
13 deletion. On the right is a cancerous cell
with deletion.
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The Two-Hit Hypothesis

• Alfred Knudson was one of the first to recognize
  tumor suppressors and form the two-hit
  hypothesis in his observations of RB in children.
• Two mutations can lead to RB
• - the first mutation is inherited and can
  affect a newborn with just a single mutation in
  one somatic eye cell.
• - the second mutation, in its non-inherited
  form, appears later in childhood.

Alfred Knudson is now widely recognized for his
research on RB and the two-hit hypothesis.
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The p53 Gene

• p53 is a gene that codes for a protein which
  decides whether a cell should repair DNA copy
  errors or die.
• Much like the RB gene, if there is a slight
  mutation or deletion of the p53 gene, a cell with
  damaged DNA can be allowed to divide, leading to
  cancer.
• More than ½ of all cancers involve some sort of
  mutation or deletion in the p53 gene.
• Environmental triggers such as viruses,
  radiation, and smoking can lead to mutations in
  the p53 gene.

The p53 gene.
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BRCA-1 and Breast Cancer

• BRCA-1 codes for a protein that is necessary for
  DNA repair.
• Mutations in BRCA-2 (a gene that is very similar
  to BRCA-1) can cause breast cancer, or lead to
  other kinds of cancer.

• BRCA-1 stands for breast cancer predisposition
  gene 1.
• It is a mutated tumor suppressor gene that, when
  inherited, has a late onset of symptoms for the
  affected individual.

A breast cancer survivor.
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Series of Genetic Changes

• Gatekeeper genes control mitosis and apoptosis
  (cell death).
• Caretaker genes control the mutation rates of
  gatekeeper genes.
• Series of genetic changes in different stages of
  cancer can help researchers to pinpoint certain
  mutations and develop prevention treatments.

Understanding genetic changes in the different
stages of colon cancer could potentially lead to
preventative treatments.
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Brain Tumors
On the left is a normal brain, and the blue mass
in the right brain is an astrocytoma.

• Astrocytomas are the most common kinds of brain
  tumors.
• They are the result of a series of single-gene
  and chromosomal changes that occur in different
  stages of the growth of the tumor.

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Colon Cancer

• Only 5 of colon cancer cases are inherited.
• Colon cancer begins with the build-up of tiny
  colon polyps, which leads to a condition called
  FAP. Colon lining cells that do not die on
  schedule build up and lead to cancer.
• Researchers have pinpointed the direct cause of
  colon cancer to be linked to a deletion in
  Chromosome 5.
• A kind of chain reaction in this mutation leads
  to others that can spread the cancer (p53, PRL-3,
  and TGF).

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Environmental Factors

• Mutating genes that help the cancer cells and
  that strongly affect the person. This can happen
  in virtually anyone.

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Carcinogens

• Carcinogens are any substance, illness or
  exposure circumstances that directly raises the
  risk of cancer.
• There is a four-grouped classifying system,
  one-four of how carcinogenic things are to
  humans.
• However many studies only prove correlations
  instead of cause and effect.

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Lowering Your Risk

• Avoid certain high-risk factors
• Chemoprevention
• Taking certain nutrients, plant extracts, or
  drugs, which include folic acids, vitamin D,
  extracts from green tea and tomatoes, and more.

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Methods to Study Cancer-Environment Links

• Population Study
• Population disease incidence in different groups
  of people. Yet too many variables make it hard
  to establish solid cause effects.

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• Case-Control Study
• People with a certain type of cancer are matched
  along with people much like them (weight, age,
  ethnicity, etc.) but who are healthy.
  Researchers then look at significant differences
  between the twos lifestyle and history.
• Prospective Study
• A study that follows two or more groups as they
  comply to a specified activity plan. They are
  continuously checked on for cancer. However some
  forms of cancer may take several years to appear.

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Diagnosis and Treatments

• After a screening test (blood or x-rays),
  symptoms occurring, or patient feels it, there
  are several options in which the person can take
  for treatment.

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• Surgery
• Simply remove the tumor, however if even one
  cancer cell is left though, a tumor will return.
• Radiation Chemotherapy
• Kills all cells that divide rapidly. This also
  kills healthy cells.
• Newer Types of Treatment
• Include inhibiting telomeres, blocking hormone
  receptors, and drawing the blood out of the
  cancer cells.
• Alternative Methods
• Prayers, herbs, etc.

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Genomic Approaches

• Breast cancer is a great example of how genes are
  helping us understand and fix the problem.
  Phenotype and Genotypes are taken into
  consideration
• Depending on the women, the breast cancer either
  has receptors for estrogen or progesterone. That
  will determine what medicine and recovering
  therapy she will receive.

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• Cancer diagnosis will continue to be based more
  heavily on DNA microarrays, which will look at
  gene expression and genotype.
• This will be able to give patients immediate
  treatments that fit their type of cancer. Also
  predicts side affects that particular patient
  will get.

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• References
• Function of Cancer Genes Discovered, Science
  Daily, May 13, 2005
• March7,2007,http//www.sciencedaily.com/releases/
  2005/05/50513224031.htm
• Lewis, Ricki, Human Genetics, New York
  McGraw-Hill, 2005
• The p53 tumor suppressor gene. National Center
  for Biotechnology Information.
•      http//www.ncbi.nlm.nih.gov. Jan 10 2007.
• Wikipedia, March 5, 2007, Free Encyclopedia,
  March 6, 2007, lthttp//en.wikipedia.org/wiki/Cance
  rgt

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• Bonus Question!
• Q What are the most common type of brain tumors?

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• A Astrocytomas