Cancer and Mutation Flashcards
(6 cards)
(l) Explain what is meant by the terms gene mutation. For gene mutation, knowledge of how substitution, addition and deletion could change the amino acid sequence (including frameshift) is required.
Gene mutation describes any change in the nucleotide sequence of DNA.
(a) Types of gene mutations
There are three types of mutation:
(i) Substitution
- Substitution is the replacement of one nucleotide pair with another pair of nucleotides.
(ii) Addition
- An addition is the insertion of one or more nucleotide pairs into a DNA sequence.
(iii) Deletion
- A deletion is a mutation in which one or more nucleotide pairs are removed from a DNA sequence.
Point mutations refer to changes in one nucleotide pair of a gene.
Effects of Gene Mutations
Base pair substitution may result in silent, missense or nonsense mutations.
(i) Silent Mutations
Silent mutations are mutations that have no effect on amino acid sequence
No observable effect on phenotype of organism.
Some substitution mutations are silent due to the redundancy / degeneracy of the genetic code.
(ii) Missense Mutations
Other substitutions may change an amino acid but have little effect on the protein because new amino acid may have properties similar to those of the amino acid it replaces.
The replacement amino acid may also be in a region of the protein where the exact sequence of amino acids is not essential to the protein’s function.
However, if the base-pair substitutions occur in a crucial area in a protein, e.g. in the active site of an enzyme, it may result in an alteration of a single amino acid that will significantly alter protein activity.
Substitutions usually results in missense mutations. This means that although a protein is still produced, the protein may not be as effective.
iii) Nonsense Mutations
A point mutation can also change a codon for an amino acid into a stop codon. It causes translation to be terminated prematurely.
This nonsense mutation results in the polypeptide formed being shorter than the polypeptide encoded by the normal gene. Nearly all nonsense mutations lead to non-functional proteins
Addition and deletion may result in frameshift mutation.
(iv) Frameshift Mutations
mRNA is read as a series of triplet nucleotide during translation, addition or deletion of nucleotide pair may alter the reading frame (triplet grouping) of the genetic message.
Frameshift mutations occur whenever the number of nucleotides inserted or deleted is not a multiple of three.
All the nucleotides that are downstream of the addition or deletion will be improperly grouped into codons. It results in extensive change in the sequence of amino acids.
The change in codons may also result in premature termination.
Unless the frameshift is very near the end of the gene, it will produce a protein that is almost certain to be non-functional.
Insertions and deletions of three nucleotide pairs result in polypeptides with additional or missing amino acids
Explain what is meant by the term chromosomal aberration. For chromosomal aberration, knowledge of numerical aberration (including aneuploidy, as in the case of trisomy 21, i.e. Down syndrome) and structural aberration (including translocation, duplication, inversion and deletion) is required.
Chromosomal aberration / chromosomal mutation is a mutation that involves a change in the structure or number of chromosomes.
Number of chromosomes (Aneuploidy)
Aneuploidy is the condition during which an organism possesses an extra chromosome (2n+1) or lacks a chromosome (2n-1).
Non-disjunction is an error during meiosis when:
A pair or pairs of homologous chromosome fail to separate during Anaphase I of meiosis or
sister chromatids fail to separate during Anaphase II of meiosis.
This results in aberrant gametes:
gamete receives two of the same type of chromosome / extra chromosome (n+1) and
gamete with no copy of a particular type of chromosome / lacks a chromosome (n-1)
If an aberrant gametes fuses with a normal gamete during fertilisation, the zygote will have an extra chromosome (2n+1) or a missing chromosome (2n-1).
Non-disjunction during anaphase I of meiosis results in all aberrant gametes. [50% of the gametes have (n+1) chromosomes and 50% of the gametes have (n-1) chromosomes].
Non-disjunction at anaphase II of meiosis results in half normal gametes and half aberrant gametes
Down’s syndrome is an aneuploid condition in humans. It is the result of an extra chromosome 21, such that each somatic cell has a total of 47 chromosomes. Down syndrome is often called trisomy 21 as there are three chromosomes 21.
Number of sets of chromosomes present in the cell (polyploidy)
Polyploidy is the condition whereby an organism acquires more than two complete sets of chromosomes.
Organisms with three complete sets of chromosomes (3n) are called triploids.
Organisms with four complete sets of chromosomes (4n) are called tetraploids.
Triploidy may arise by the fertilisation of an abnormal diploid egg produced by non-disjunction of all its chromosomes with a normal sperm.
Tetraploidy could result from the failure of 2n zygote to divide after replicating its genetic material. Subsequent normal mitotic divisions would then produce a 4n embryo.
Deletion
Deletion occurs when a chromosomal fragment is lost. Certain genes will be missing from the affected chromosome.
Duplication
A duplication occurs when a detached chromosomal fragment from a sister chromatid become attached as an extra fragment to a non-sister chromatid of a homologous chromosome / the other sister chromatid during meiosis.
Inversion
Inversion occurs when a fragment of a chromosome breaks off and reattaches to the original chromosome in a reverse orientation.
Translocation
Translocation occurs when a chromosomal fragment breaks and joins with a non-homologous chromosome
(m) Explain how gene mutations can result in diseases (including sickle cell anaemia).
Diseases associated with gene mutation
(i) Sickle cell anaemia
Autosomal recessive disorder
The genetic basis of sickle-cell anaemia is due to mutation of a single base pair in the gene that codes for one of the polypeptides of haemoglobin.
The substitution of a single nucleotide, from CTT to CAT in the DNA’s template strand of chromosome 11 leads to a change in the codon of mRNA.
The original amino acid coded for is glutamate is changed to valine at the sixth position.
Glutamate and valine are amino acids with very different properties. Glutamate is hydrophilic while valine is hydrophobic.
The mutated haemoglobin tends to polymerise into long rigid chains when not bound to oxygen.
The long fibres distort the membrane of the red blood cell giving it its distinct sickle shape.
This results in the decreased oxygen-carrying ability of the red blood cells.
Sickled red blood cells may clump and clog small blood vessels, leading to organ damage and even paralysis.
In individuals who are homozygous for the mutant allele, altered haemoglobin results in the sickling of red blood cells and produces the multiple symptoms associated with sickle-cell disease, such as shortness of breath and dizziness.
(p) Identify the causative factors, including genetic, chemical carcinogens, ionising radiation and loss of immunity, which may increase the chances of cancerous growth.
(c) Causative factors
Cancer usually develops when cells escape normal cell cycle due to oncogenes or mutated tumour suppressor genes. There are various factors, physical, chemical and biological, that can cause mutation of these genes and increase the chances of cancer.
(i) Physical factors:
Ionising radiation: α / β / γ radiation, X-ray
o Radiation causes formation of chemically active ions in the cells which are capable of damaging and breaking DNA.
Ultra-violet light
o Absorption of UV causes DNA to increase in energy level. This causes the nitrogenous bases to be more reactive and react with surrounding molecules.
(ii) Chemicals factors (carcinogens): ethidium bromide, asbestos, coal dust
Mutagens that cause chemical changes in bases resulting in incorrect base pairing, results in insertion or deletion of base pair.
(iii) Biological:
Viruses: retrovirus, DNA virus. o These viruses alter DNA sequence of host leading to formation of oncogenes, e.g. Human papilloma virus causing cervical cancer.
Fungus
o Stored grains and peanuts contaminated with Aspergillus flavus, fungal poison called mycotoxins can cause liver cancer.
(iv) Genetic factor: inherited cancer-causing-gene from parent
Mutated genes such as either oncogenes or mutated tumour suppressor genes found in gametes of parents.
o e.g. Colon cancer usually runs in the family
(v) Loss of immunity
Immunodeficiency leading to frequent and recurrent infections thus increasing susceptibility to some cancers.
o e.g. Kaposi’s sarcoma (Kaposi sarcoma herpesvirus) in AIDS patients and liver cancer (Hepatitis virus)
(q) Explain how the loss of function mutation of tumour suppressor genes, including p53, and gain in function mutation of proto-oncogenes, including ras, results in uncontrolled cell division.
Tumour suppressor genes
Tumour suppressor genes encode proteins that inhibit cell division or promote apoptosis (controlled cell death).
The loss-of-function mutation of tumour suppressor genes to mutated tumour suppressor genes leads to no protein product or decrease in amount of protein product or permanently deactivated proteins. This will result in uncontrolled cell division, possibly leading to cancer.
Loss-of-function mutation result in a recessive allele as the normal dominant allele encodes functional protein. Two alleles of a gene need to be mutated to have an effect.
o E.g. p53 gene codes for p53 protein, is a transcription factor that promotes synthesis of protein that triggers cell cycle arrest or promote apoptosis when DNA damage is detected.
Proto-oncogenes
Proto-oncogenes encode proteins that stimulate normal cell division.
The gain-of-function mutation of proto-oncogenes to oncogenes leads to increase in amount of proto-oncogene’s protein product or permanently activated proteins.
This will result in uncontrolled cell division, possibly leading to cancer.
Gain-of-function mutation result in a dominant allele as the effect of the normal allele is masked by the mutated allele. Only one allele of a gene needs to be mutated to have an effect.
o E.g. Ras gene codes for Ras protein, is a G protein that relays a signal from growth factor receptor on cell surface membrane to a cascade of protein kinases which result in normal cell division.
(r) Describe the development of cancer as a multi-step process that includes accumulation of mutations, angiogenesis and metastasis.
When the control of the cell cycle is defective, cells divide uncontrollably. These cells are called cancer cells.
Cancer cells exhibit a loss of anchorage dependence.
Cancer cells exhibit a lack of density-dependent inhibition.
As a result, a clump of overlapping cells is formed called tumour.
Multi-step process of cancer development
Several mutations must occur for a cell to become fully cancerous.
Cancer results from an accumulation of mutations and mutations occur throughout life.
A person may inherit a form of one or more genes that makes him or her more likely to develop a specific type of cancer. On top of this, he or she may acquire other mutations because of exposure to cigarette smoke, excess sunlight, or viruses. These usually result in the appearance of at least one active oncogene and the mutation or loss of several tumour-suppressor genes.
Furthermore, since mutant tumor-suppressor alleles are usually recessive, in most cases mutations must knock out both alleles in a cell’s genome to block tumor suppression. On the other hand, alleles of oncogenes are usually dominant.
In many malignant tumors, the gene for telomerase is activated. This enzyme prevents the shortening of telomeres during DNA replication. Production of telomerase in cancer cells removes a natural limit on the number of times the cells can divide.
These mutations result in the uncontrolled proliferation of cells forming tumour.
Tumour angiogenesis is required before tumours can grow beyond a few millimetres in diameter. This is the process by which new blood vessels sprout and grow from pre-existing vessels in the surrounding normal tissues. This allows nutrients to be brought to tumour cells in order to facilitate their growth
After angiogenesis has occurred, cancer cells invade surrounding tissues.
The cancer cells then enter the circulatory system, and metastasize to distant sites.
