MCB Lecture 23 Cancer Flashcards
What are the Big 5 cancers?
Prostate Bowel Breast Skin melanoma Lung
What are the cancer trends in Australia currently?
For the past 20 years, incidence has increased, but the rate has stayed roughly constant
How many deaths per year do the Big 5 represent collectively?
40,000
Has there been any improvement in the cancer incidence rate in Australia?
Yes in some cancers there has been some improvement in morbidity
However, in pancreatic and lung, there has been little to no improvement
What does the term cancer refer to?
Cancer is a generic term for a collection of generic terms
What are the four general types of cancer?
- Carcinoma: cancer of epithelial cells
- Sarcoma : cancer of connective tissue
- Lymphoma: cancer of lymphatic system
- Leukaemia: cancer of blood cells
What are sarcomas?
Cancers of connective tissue
What are carcinomas?
Cancer of epithelial cells
What are leukaemias?
Cancers of blood cells
What are lymphomas?
Cancer of the lymphatic system
What is the relationship between cancer incidence and age?
As age increases, cancer incidence increases
Describe delayed onset
Cancer onset will be a number of years after the exposure to the carcinogen
What are the two types of tumours?
Benign and malignant
What is a benign tumour?
Give an example
Benign tumours do not invade healthy tissues and cause spread of cancerous cells
Cannot create new tumours
Eg. Freckles and moles
What is a malignant tumour?
These tumours can invade healthy tissues, metastasise and cause more tumours
What is metastasis?
This is when cancerous cells are mobile. They move from one area to another.
This may be from the origin to elsewhere, or not
What is the name for the process where a normal cell becomes cancerous?
How does this occur?
Malignant transformation
This occurs when there is a build up of mutations, eventually leading to a cell that has uncontrolled cell division etc.
What is apoptosis?
Programmed cell death
What is senescence?
When a cell is still alive, but is not still growing
What are the two main pathways to tumourigenesis?
- Activation of tumour promoting
2. Deactivation of tumour suppressing
Give a general description of the tumour promoting pathway
Mutation relating to a proto-oncogene
Proto oncogene becomes an oncogene –> increase is cell proliferation
What is an oncogene?
An oncogene is a gene relating to functions such as cell proliferation that has been over expressed somehow, turning a normal cell into a cancerous cell
What is a proto-oncogene?
This is the normal version of the cancer causing gene.
It has a role in cell proliferation
What are the 5 different ways that proto-oncogenes can be turned on?
- Mutation causing hyperactive protein made in normal amounts
2 mutation in promoter region causing normal protein to be made in increased amounts - Gene replication: multiple copies of the gene
- Chromosome rearrangement:
a. Gene comes near regulatory sequence
b. fusion to an actively transcribed gene causing a hyperactive protein
What does a deletion/SNP in a proto-oncogene lead to?
The gene product may have increased activity
Now, the same amount of the protein has a bigger effect on the cellular processes
What does a mutation in the regulatory sequence lead to?
Overproduction of a normal gene
What does gene amplification of proto-oncogenes lead to?
Overproduction of a normal protein
What does chromosome rearrangement involve?
What are the two examples of chromosome rearrangement?
a. Sequence fused near regulatory sequence –> Burkit’s lymphoma
b. Sequence fused to an actively transcribed gene -> Chronic Myeloid Leukaemia
How is Burkitt’s lymphoma caused?
Fusion of regions from Cr. 8 to Cr. 14
Myc fused to immunoglobulin regulatory region
How is Chronic Myeloid Lymphoma caused?
Regions from Cr. 9 and Cr. 22 become spliced
Abl gets spliced to bcr
The Philadelphia chromosome
Which two regions are fused in the Philadelphia chromosome?
What does each region do?
bcr: break point cluster region
C-Abl: gene for tyrosine kinase receptor
Bcr-c-abl gene for protein with increased tyrosine kinase activity
Which two regions are fused on the chimeric chromosome that causes Burkitt’s Lymphoma?
What does each region do?
Immunoglobulin regulatory region
Myc: gene for transcription factor involved with cell proliferation, growth, angiogenesis
Briefly describe the tumour suppressing pathway
When mutations occur in the tumour suppressing pathway, genes that are normally involved with apoptosis and senescence are turned off. Cell don’t die
Explain the Knudson Two Hit Model
Since we have two copies of each gene, it requires a mutation in both to cause cancer
What is it called when the second copy of the gene is mutated?
Loss of heterozygosity
What are the genetic mechanisms for loss of heterozygosity?
- Non disjunction
b. followed by chromosome replication - Mitotic recombination
- Deletion
- Point mutation
- Gene conversion
What does non-disjunction lead to?
Only one chromosome in the cell, only one copy of the gene
What does non-disjunction, then chromosome duplication lead to?
Two copies of the mutated gene
What does mitotic recombination lead to?
The mutated gene replaces the normal gene on the other chromosome
What does gene conversion lead to ?
Normal gene converted to the mutated one
How does deletion lead to L.O.H.?
Loss of the normal allele
How does point mutation lead to L.O.H.?
Loss of the normal allele
How can both genetic and epigenetic changes lead to L.O.H.?
Genetic: mutation in the normal allele
Epigenetic: silencing of the normal allele, so only the mutated one is active
What is p53?
This is a tumour suppressor gene
The mutated version is extremely common in cancers
What is normal function of p53?
It’s a transcription factor -> binds to DNA and alters expression of genes
Normal function is cell cycle control DNA repair apoptosis Genetic stability Inhibition of angiogenesis
Where are most mutations of p53 localised?
In the DNA binding region of the transcription factor
What happens when p53 mutates?
When the gene for p53 mutates, the protein has a different DNA binding site
The transcription factor will bind differently to promoter regions
Explain Li-Fraumeni syndrome
This is a syndrome where people are born with one copy of a mutant allele of p53
This means they only have to receive one hit and they will develop the cancer
Does the p53 product undergo modifications?
Yes, post- translational
What are the hallmarks of cancer?
- Uncontrolled cell proliferation
- No cell death
- Angiogenesis, blood supply to tumour
- Avoids signals from growth repressors
- Metastasis
- Immortality
What is Myc?
This is a gene coding for a transcription factor that is involved with regulation of cell proliferation and angiogenesis
What is the structure of p53?
Tetramer
Describe the features of the loss of function mutations of p53
Some mutations of p53 are dominant negative
This means a single hit it sufficient to lose the tumour suppressor activity
