Oncogenes & Tumour Suppressor Genes

How many different types of cancer

> 100

Cancer cells are heterogenous. How do they vary?

Cure rate & treatment response

Genetic makeup between cells within the same tumour

Presence of cycling vs. resting cells

Ability to spread (metastasis)

Define gene

The basic unit of heredity passed from parent to child

On what 4 levels can we regulate genes

DNA to RNA:

• Transcription

RNA

• Splicing

• mRNA stability

RNA to Protein

• Translation

Protein

• Protein stability

• Post translational modifications

• Cellular localization

Cancers are genetic and epigenetic diseases. Which part (genetic/epigenetic) can be reversed

Epigenetic change can eb reversed

(In genetic change, it is irreversibly fixed in the genetic material of the tumour cell)

Give 2 examples of genetic changed 

Point mutations - Single nucleotide base changes

Gross chromosomal rearrangements

Do point mutations affect DNA/RNA/Protein

All 3 - Present in the DNA, transcribed into RNA – can result in changes to the encoded protein

Name & explain 3 examples of types of point mutations

Nonsense mutation: Altered codon encodes a termination codon → shortened protein

Missense mutation: Altered codon encodes a different amino acid → non-functional / hyperactive protein

Silent mutation: Altered codon encodes for the same amino acid

What is the consequence of Gross chromosomal rearrangements

increased/decreased copy number and gene expression

Name these chromosome rearrangements

Give 4 mutagenic outcomes of DNA double strand break repair

Explain how micronuclei form & what goes wrong with them

1. A chromosome gets left behind during cell division → forms a micronucleus.

2. Micronucleus is defective → its envelope often breaks.

3. DNA inside gets massively damaged.

4. In the next divisions, the shattered DNA gets randomly stitched back together.

Result: chromosome rearrangements (very unstable, cancer-promoting).

Explain how mitotic bridges form & what goes wrong with them

1. Two chromosome ends fuse → form a dicentric chromosome (two centromeres).

2. During division, the two centromeres get pulled apart → forms a DNA bridge.

3. The bridge breaks due to mechanical stress or enzymes like TREX1.

4. Broken ends are uncapped → they fuse again after DNA replication.

5. This cycle repeats (breakage–fusion–bridge cycle) → causes ongoing DNA rearrangements.

Give 2 examples of epigenetic changes that can occur in cancer 

DNA methylation

Histone modifications

(both affect gene expression)

Process of DNA methylation

DNA methylation is a biochemical process where the 5th carbon present in cytosine is enzymatically methylated

Enzymes catalysing DNA methylation are…

DNMT1

DNMT3A

DNMT3B

DNA can be passive or active with the use of what

TET

How ca DNA methylation affect tumour suppressor genes

Give 3 examples of histone modifications:

• 2 repressive modifications

• 1 activation modification

Repressive: H3K9me3 & H3K27me3

Activation: H4K16ac

What creates & removes histone modifications

Enzymes

What enzymes are in charge of changing the chromatin conformation from closed → open → closed

What therapy can be used for genetic changes in cancer cells

Gene therapy

What therapy can be used forepi genetic changes in cancer cells

Targeting enzymes with small molecules → reverse epigenetic change

What are the 2 types of genes altered in cancer cells

Oncogenes

Tumour suppressor genes

Give 3 examples of oncogenes

myc, ras, abl

Give 3 examples of Tumour suppressor genes (TSG)

RB, p53, BRCA1, BRCA2

Are oncogenes & tumour suppressor genes dominant/recessive

Oncogenes act in a dominant manner

Tumour suppressors are recessive

Difference between Ras GDP & Ras GTP

RAS-GDP = OFF. When RAS is bound to GDP, it is inactive → no growth signal.

RAS-GTP = ON. When RAS binds GTP, it turns on → sends a strong “grow and divide” signal.

Why is Ras an important molecule clinically

Mutations in Ras and in the Ras pathway are very common in human cancers

What is a change that can occur which would make Ras an oncogene

If it becomes a mutant protein that lacks GTPase activity, it is active [‘on’] all the time

Burkitt’s lymphoma is cancer of what

Cancer of lymphocytes

Burkitt’s lymphoma is common where in the world

certain parts of Africa

What gene is involved in Burkitt’s lymphoma & what mutation occurs to it

c-MYC gene translocated from chromosome 8 to chr. 14

What is the result of c-MYC gene translocation in Burkitt’s lymphoma

Enhanced production of Myc protein → Stimulates cell proliferation → tumour formation

Myc regulates proliferation through what molecules

↑ CDKs - cyclin dependent kinases

↓ Inhibits p15

↓ Inhibits p21

What is Li-Fraumeni syndrome

A rare cancer-prone syndrome where people are born with a germline mutated copy (allele) of p53 so their risk of cancer is much higher because they only need 1 somatic mutation in the other copy (allele) of p53 gene.

Leads to early onset of variety of cancers – of blood, breast, bone, lung and skin

What does p53 normally do

It is a Transcription factor → Mediates Cellular stress signals

How does a p53 mutation lead to cancer

Mutation in p53 leads to loss of ability to arrest cell cycle progression after DNA damage

Cell continues to divide in the presence of DNA damage

Increase in mutations in genome – genome instability

Also become resistant to some chemotherapeutic agents

True/False: Multiple lesions are required to cause most cancers

True

What shows that Cancer genomes are unstable

Deep sequencing approches of genomes have revealed high degree of intratumural heterogeneity