Transcript The Genetics of Cancer

Overview of Cancer
Amit M. Patel, MS
William Simmons, PhD
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?
Cancer is a disease of the cell cycle
Three main checkpoints in the cell cycle
•2001 Nobel Prize was awarded to 3 scientists who studied
genes that regulate the cell cycle
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3.
1. Is cell the correct size?
Is DNA damaged?
2. Is DNA fully replicated?
Is DNA damage repaired?
2.
3. Have spindle fibres
formed?
Have they attached to
chromosomes correctly?
Types of genes which may mutate to cause cancer:
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Tumour suppressor genes
oncogenes
DNA repair genes
telomerase
p53
The environment:
Some environmental agents associated with cancer are:
• Viruses
• Tobacco smoke
• Food
• Radiation
• Chemicals
• Pollution
Viruses
Viruses—mostly in the form of DNA viruses—have been
causally linked to cancer.
• human papillomaviruses—primarily types 16 and 18,
which are sexually transmitted—have been linked to
cervical cancer;
• more than 25 other types of papillomaviruses have been
linked to cancer as well
• hepatitis B and C—linked to cancer of the liver
• human immunodeficiency virus (HIV)—linked to Kaposi's
sarcoma and lymphoma
• retroviruses—linked to cancers in animals other than
humans
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
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
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.
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:
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benzene (myelogenous leukaemia)
arsenic containing pesticides (lung cancer)
polychlorinated biphenyls (liver and skin cancers)
mineral oils (skin cancer)
mineral fibres (lung cancer and mesothelioma)
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%.
Cancer terminology
Classification by tissue type:
• carcinoma
epithelial cell
90% of all tumours
derived from ectoderm (mostly) or
endoderm (some)
• sarcoma
connective tissue
2% of all tumours
derived from mesoderm
• leukaemia
circulatory or lymphatic
8% of all tumours
derived from mesoderm
Classification by the type of cells:
• Adenomatous cells
ductal or glandular cells
• Squamous cells
flat cells
• Myeloid
blood cell
• Lymphoid
lymphocytes or macrophages
Cancer terminology
Classification by the site of origin of the tumour:
• Breast: carcinoma of ductal, medullary, papillary, etc. cells
• Lung:
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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,
Cancer terminology
Benign tumours
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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
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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
Tumour suppressor genes
• The gene’s 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.
Knudsen’s “two hit” hypothesis
retinoblastoma
retinoblastoma
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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 correlation:
most mutant RB1-alleles show premature termination codons and are
associated with almost complete penetrance (>95%) 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 wildtype transcript are associated with incomplete penetrance (<75%) and low
expressivity (mean of less than 2 tumor foci)
RB1
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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.
Breast Cancer
“Why do so many of my relatives have breast cancer...is this just plain bad luck or what?”
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:
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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.
Breast Cancer
But its more complicated than that!
oncogenes
• Cellular oncogene c-onc
• Viral oncogene v-onc
• Proto-oncogene, activated by mutation to
c-onc
Proto-oncogene activation
Types of proto-oncogene
• Growth factor
e.g. SIS oncogene (PDGF)
Types of proto-oncogene
• Growth factor receptor
e.g. tyrosine kinase receptors
Types of proto-oncogene
• G proteins
e.g. ras
Types of proto-oncogene
• Nuclear transcription factors
e.g. MYC
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
Transformation is a
multistep process
Transformation is a multistep process
Colorectal Cancer
• 11% of cancerrelated deaths
• Tumor
progression may
take 10-35 years
• Adenomatous
polyp develops
into carcinoma
Chromosome changes in colorectal cancer
Cancer karyotype
Stable karyotype
reading
URLs:
• http://www.infobiogen.fr/services/chromcancer/Kprones/RbKprID10031.html
• http://cgap.nci.nih.gov/
• http://www.intouchlive.com/home/frames.htm?http://www.intouchlive.com/ca
ncergenetics/&3
• http://bioinformatics.weizmann.ac.il/hotmolecbase/entries/p53.htm
Books:
• Concepts of Genetics, Klug and Cummings, chapter 23
• Molecular Biology of the Cell