Cancer Genetics and biological processes

Cancer genetics

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 Unit 5
Genetics & Biological Processes
Lecture #3

5.1 Extranuclear inheritance.
5.2 Developmental genetics.
5.3 Cancer genetics.

Cigarette smoking and lung cancer

2. Genetic Basis of Cancer
– Concepts
Cancer is a group of genetic diseases affecting fundamental aspects of
cellular function, including DNA repair, cell-cycle regulation, apoptosis, and
signal transduction.
Most cancer-causing mutations occur in somatic cells; only about 1% of
cancers have a hereditary component.
Mutations in cancer-related genes lead to abnormal proliferation and loss of
control over how cells spread and invade surrounding tissues.
The development of cancer is a multistep process requiring mutations in
genes controlling many aspects of cell proliferation and metastasis.
Cancer cells show high levels of genomic instability, leading to the
accumulation of multiple mutations in cancer-related genes.
Mutations in proto-oncogenes and tumor-suppressor genes contribute to the
development of cancers.
Environmental agents contribute to cancer by damaging DNA.

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Chemicals signals regulate cell
division

4. Chemical signals Regulate Cell Division
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Genetic Basis of Cancer
Cancer is a disease characterized
by uncontrolled cell division.

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Mutation
A heritable change in the genetic material
Essential to the continuity of life
Source of variation for natural selection
New mutations are more likely to be harmful
than beneficial
DNA repair systems reverse DNA damage
Cancer is a disease caused by gene mutations
Gene mutations alter the DNA sequence
Point mutation affects only a single base pair
2 basic alterations: 1. Change base sequence
2. Add or remove nucleotide(s)

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Examples
Change base sequence
Base substitution




Add or remove a single base pair
5’ – CCCGCTAGATA – 3’ → 5’ – CCCGCGAGATA – 3’

3’ – GGGCGARCTAT – 5’ 3’ – GGGCGCTCTAT – 5’
5’ – GGCGCTAGATC – 3’ → 5’ – GGCAGCTAGATC – 3’

3’ – CCGCGATCTAG – 5’ 3’ – CCGTCGATCTAG – 5’

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Gene mutations may affect amino acid sequences
Silent mutation
Does not alter the amino acid sequence
Genetic code is degenerate
Missense mutation
Changes a single amino acid in a polypeptide
May not alter function if substituted amino acid is
similar in chemistry to original
Sickle-cell disease is the result of a single amino acid
substitution

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Gene mutations may affect amino acid sequences …….

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Nonsense mutation
Change from a normal codon to a stop or termination
codon
Produces a truncated polypeptide
Frameshift mutation
Addition or deletion of nucleotides that are not
multiples of 3
Completely different amino acid sequence
downstream from mutation
Gene mutations may affect amino acid sequences …….

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Gene mutations may affect amino acid sequences …….

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Germ-line or somatic cell
mutations
Exact time and location of a mutation is critical to
severity of effect and to the ability to pass on the
mutation
Germ-line cells give rise to gametes
Can occur in a sperm or egg cell or in cell that gives
rise to eggs and sperm
Somatic cells are all other body cells
Can occur early or late in development
Genetic mosaic results from patches of mutated tissue

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Spontaneous or induced
mutations
Spontaneous mutations result from
abnormalities in biological processes
Rates vary from species to species and from
gene to gene
Expected rate of background mutation
approximately 1 mutation for every 1 million
genes

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Spontaneous or induced mutations ….

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Induced mutations are brought on by
environmental agents
Mutation rate higher than spontaneous mutation
rate
Mutagens are chemical or physical agents
Can alter DNA in various ways
Spontaneous or induced mutations ….

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Spontaneous or induced mutations ….

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Mutagens alter DNA
Disrupt pairing by…
Modifying nucleotide structure
Nitrous acid deaminates bases so that modified bases do not
pair with appropriate nucleotide
Using base analogue similar to particular bases
Akylating bases
Interfering with replication
Inserts between bases and distort the helix

18. Deamination and mispairing of modified bases by a chemical mutagen

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DNA repair
All living organisms must have the ability to repair
changes that occur in DNA in order to minimize mutation
Requires…
DNA damage be detected
Repair of DNA damage
Types of repair
Direct repair
Enzyme removes a modification (for example an alkyl group)
Altered DNA strand removed and new segment synthesized
More common
Nucleotide excision repair
Methyl-directed mismatch repair

20. Genetic Basis of Cancer
Cancer is one of the most feared
diseases

Disease of multicellular organisms
that is characterized by uncontrolled
cell division

e.g. In United States alone, over a
million new cases and over 500,000
related deaths per year
prostate cancer = most common in males
breast cancer = most common in females
Stopped!

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22. What is Cancer?
Cancer is a group of diseases characterized by uncontrolled cell
growth and spread of abnormal cells
It is a genetic disease at the cellular level.
More than 100 kinds of human cancers have been identified, and they
are classified according to the type of cell that has become cancerous.
Though cancer is a diverse collection of many diseases, some
characteristics are common to all cancers.
Cancer progresses through several different stages
Hyperplasia = Increase in cell number
Metastasis = Cell migration
Malignancy = Cell invasiveness

23. Model for cancer progression.

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25. Carcinogens
Carcinogens are agents that cause mutations
Human tumors
Less than 10% are hereditary or familial
More than 90% arise spontaneously
Spontaneous mutations result from abnormalities in
biological processes
Induced by human-created and natural carcinogens

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Carcinogens
About 80% of all human cancers are related to exposure to
carcinogens
Agents that increase the likelihood of developing cancer
Most carcinogens, such as UV light and certain chemicals in cigarette
smoke, are mutagens that promote genetic changes in somatic cells
DNA alterations can lead to effects on gene expression that ultimately
affect cell division, and thereby lead to cancer
Cancers originate from a single cell
Cell and its offspring mutate so cells grow abnormally
Tumor- an overgrowth of cells with no useful purpose
Tumor may begin as benign or pre-cancerous
Do not invade or spread

27. Genes That Cause Cancer
Oncogenes and Tumor-Suppressor Genes

A gene that causes cancer is called oncogene
(“tumor genes”)
A normal gene with potential to become an oncogene
is called a proto-oncogene
For a proto-oncogene to become an oncogene – a mutation
must occur in cell’s DNA
Changes in genes whose products inhibit cell division
are also involved in cancer – these genes are called
tumor-suppressor genes
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28. How a proto-oncogene can
become an oncogene
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Proto-oncogene
Normal gene that, if mutated, can become an
oncogene
4 common genetic changes
1.Missense mutations
2.Gene amplifications
3.Chromosomal translocations
4.Retroviral insertions

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Missense mutations
Chemical mutagens have been shown to cause
missense mutations leading to cancer

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Gene amplifications
Abnormal increase in
copy number results in
too much of the
encoded protein

Many human cancers
are associated with the
amplification of
particular proto-
oncogenes

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Chromosomal translocations
Two different chromosomes
break, and the ends of the broken
chromosomes fuse with each
other incorrectly
Very specific types of
chromosomal translocations have
been identified in certain types of
tumors
Chimeric genes are composed of
two gene fragments fused
together

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34. Retroviral insertions
Viral DNA may insert into a host
chromosome in such a way that a viral
promoter and response elements are
next to a proto-oncogene
May result in the overexpression of the
proto-oncogene, thereby promoting
cancer
Alternatively, a virus may cause cancer
because it carries an oncogene in the
viral genome

Majority of cancers are caused by
mutagens
A few viruses are known to cause
cancer in plants, animals, and
humans
Some viruses may cause cancer by
modifying genes in the host cell
Others carry oncogenes in the viral
genome

35. Tumor-suppressor gene
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Tumor-suppressor genes
Normal role to prevent cancerous growth
Proteins encoded by tumor-suppressor genes
usually have one of two functions
1.Proteins that maintain the integrity of the genome by
monitoring and/or repairing alterations in the
genome
Checkpoint proteins check the integrity of the genome and
prevent a cell from progressing past a certain point in the
cell cycle
2.Proteins that are negative regulators or inhibitors of
cell division
Their function is necessary to properly halt cell division
otherwise cell division is abnormally accelerated

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Loss of tumor-suppressor gene function
3 common ways
Mutation occurs specifically within a tumor-
suppressor gene to inactivate its function
Chromosome loss may contribute if the missing
chromosome carries one or more tumor-suppressor
genes
Abnormal methylation of CpG islands near promoter
regions

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Cancer is a series of changes
Cancer usually requires multiple genetic
changes to the same cell
Begin with a benign genetic alteration that, over
time and with additional mutations, leads to
malignancy
Malignancy can continue to accumulate genetic
changes that make it even more difficult to treat

39. Carcinogens

40. Inheritance and Environment
Both Can Cause Cancer
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41. Cancer Treatments
Remove or Kill Abnormal Cells
Traditional cancer treatments:

Surgery – surgical removal of tumor

Chemotherapy – drugs, usually delivered intravenously to stop
cancer cells in body from dividing

Radiation – uses directed streams of energy from radioactive
isotopes to kill tumor cells in limited areas

Surgery followed by radiation and/or chemotherapy has now
become fairly routine.
Immunotherapy, bone marrow transplants, and other methods are under
investigation.


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42. Cancer Risks and Prevention
Choices a person can make to reduce cancer
risk

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43. Reading list:
1. Hyde 2009, Ch 22
2. Brooker et al.2008, Ch 14/14.3

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