MCB Lecture 23 Cancer Flashcards by Eleanor Nicklason

What are the Big 5 cancers?

Prostate
Bowel
Breast
Skin melanoma
Lung

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What are the cancer trends in Australia currently?

For the past 20 years, incidence has increased, but the rate has stayed roughly constant

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How many deaths per year do the Big 5 represent collectively?

40,000

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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

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What does the term cancer refer to?

Cancer is a generic term for a collection of generic terms

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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

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What are sarcomas?

Cancers of connective tissue

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What are carcinomas?

Cancer of epithelial cells

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What are leukaemias?

Cancers of blood cells

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What are lymphomas?

Cancer of the lymphatic system

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What is the relationship between cancer incidence and age?

As age increases, cancer incidence increases

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Describe delayed onset

Cancer onset will be a number of years after the exposure to the carcinogen

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What are the two types of tumours?

Benign and malignant

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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

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What is a malignant tumour?

These tumours can invade healthy tissues, metastasise and cause more tumours

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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

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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.

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What is apoptosis?

Programmed cell death

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What is senescence?

When a cell is still alive, but is not still growing

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What are the two main pathways to tumourigenesis?

Activation of tumour promoting

2. Deactivation of tumour suppressing

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Give a general description of the tumour promoting pathway

Mutation relating to a proto-oncogene

Proto oncogene becomes an oncogene –> increase is cell proliferation

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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?

1. Non disjunction b. followed by chromosome replication 2. Mitotic recombination 3. Deletion 4. Point mutation 5. 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?

1. Uncontrolled cell proliferation 2. No cell death 3. Angiogenesis, blood supply to tumour 4. Avoids signals from growth repressors 5. Metastasis 6. 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