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Biology of Cancer > Introduction to Tumour Suppressor genes > Flashcards

Introduction to Tumour Suppressor genes Flashcards

1
Q

What do tumour suppressor genes (TSGs) do?

A
  • Encode proteins that maintain checkpoints in the cell cycle and to control genome stability
  • Inhibit replication and proliferation of damaged cells
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2
Q

How do TSGs carry out their function

A
  • DNA damage repair
  • Apoptosis
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3
Q

Which TSGs carry out DNA damage repair?

A
  • MLH1
  • BRCA1/2
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4
Q

Which TSG carries out apoptosis?

A

TP53

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5
Q

When and who discovered TSGs?

A

Henry Harris in 1969 through somatic cell hybridisation

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6
Q

When was the first TSG identified?

A
  • In 1986, the RB1 gene was identified
  • It causes retinoblastoma and it is a dominant gene
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7
Q

What is the Knudson’s two-hit hypothesis in TSG inactivation?

A
  • Discovered by Alfred Knudson in 1971
  • Most loss-of-function mutations that occur in TSGs are recessive
  • This is because typically, one normal allele is sufficient for cellular control
  • This means that both copies on the homologous TSG need to be mutated in order for cancer to occur
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8
Q

How does TSG inactivation occur for heritable genes?

A
  • In a normal cell, there needs to be 2 mutations to lead to cancer
  • In a germline cell, there is already 1 mutation which is inherited, therefore only 1 more mutation needs to occur to lead to cancer
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9
Q

What are mutations in both alleles called?

A

Loss of heterozygosity

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10
Q

What are 4 functions of TSGs?

A
  1. Act as oncogene antagonists
  2. Block cell proliferation (through cell cycle inhibitors and activation/repression of transcription factors
  3. Induce apoptosis
  4. DNA repair
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11
Q

What do DNA repair genes do?

A
  • Encode DNA repair enzymes which continuously monitor chromosomes to detect any damage caused by carcinogens or errors in DNA replication
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12
Q

What is an example of damage that DNA repair enzymes fix?

A
  • Double strand breaks caused by ionising radiation
  • Repaired by homologous recombination
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13
Q

What is the effect if the DNA repair gene loses function?

A
  • Loss of gene results in acquisition of more mutations
  • Defect of gene results in genomic instability and the acceleration in activation of oncogenes and loss of TSGs
  • Tumours arising in patients as a result of inherited defects in DNA repair genes tend to have a very high mutational load
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14
Q

What are the BRCA1/2 genes?

A
  • DNA repair genes that encode proteins that repair DNA double strand breaks through homologous recombination
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15
Q

Which cancers do BRCA1/2 increase the risk of?

A
  1. Female/Male breast cancer
  2. Ovarian cancer
  3. Melanoma
  4. Prostate cancer
  5. Pancreatic cancer
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16
Q

How are single strand breaks repaired by BRCA1/2?

A

They undergo base excision repair (BER) using the enzyme poly ADP-ribose polymerase (PARP)

17
Q

What is synthetic lethality?

A
  • Occurs when the inhibition of two genes is lethal while the inhibition of each single gene is no
  • Can be harnessed to selectively treat cancer by identifying inactive genes in a given cancer and targeting their synthetic lethal partners.
18
Q

How does synthetic lethality work to treat BRCA1/2 mutations in cancer?

A
  • PARP inhibitors are used to inhibit PARP1 which results in an accumulation of single strand breaks
  • This accumulation also leads to an accumulation in double strand breaks
  • This draws the BRCA mutated cells to the site
  • However, because they are mutated they’re unable to repair so the cell dies
  • This stops cell growth and therefore tumour growth
19
Q

What are 4 examples of PARP inhibitors?

A
  1. Olaparib
  2. Rucaparib
  3. Niraparib
  4. Talazoparib
20
Q

What does the TP53 gene do?

A

Produces p53 protein

21
Q

What does p53 protein do?

A
  • Acts as tumour suppressor to regulate cell division so there is no unregulated growth
  • Located in cytoplasm and nucleus and binds to DNA
  • Detects cellular stress and DNA damage and either signals for repair or apoptosis depending on the state of the cell
22
Q

Why is p53 referred to as ‘Guardian of the Genome’

A

It regulates cell division so no uncontrolled cell growth occurs therefore no tumours form

23
Q

Why are the levels of p53 low in normal cells?

A

The levels are low so they can be tightly regulated, if they were high, it is possible that they could work too much which would lead to excess apoptosis which could result in tissue damage

24
Q

How is p53 regulated?

A
  • It is regulated by MDM2 gene which produces MDM2 protein and binds to p53
  • This forms a complex which targets p53 to destruction in lysosomes
  • This allows p53 to work via negative feedback
25
Q

Why is the TP53 gene mutation important?

A
  • Over 50% of cancers contain mutations in TP53
  • Most commonly affected TSG in human cancer
  • In some cancers, TP53 mutations correlate with the pathological stage of cancer
26
Q

Why is the TP53 mutation different to other TSG mutations?

A
  • In most TSG mutations, both copies of the gene need to be mutated to result in loss of function (recessive)
  • However, in TP53, the mutation of only one copy can still have effects on the gene by reducing its function (dominant negative)
27
Q

What does the RB1 gene do?

A

Encodes retinoblastoma (Rb) protein

28
Q

What does Rb protein do?

A
  • Prevents cell growth by inhibiting cell cycle until the cell is ready to divide
  • It is phosphorylated to allow inactivation of E2F1 to prevent excess cell growth
29
Q

What happens if RB1 is mutated?

A

Rb protein loses its regulatory functions

30
Q

What is retinoblastoma?

A
  • Childhood eye cancer
  • Affects 1 in 20,000 children
  • 80 cases/year
  • 90% of cases develop before 5yrs old
  • Treated with surgery/radiotherapy
  • 98% of cases are cured
31
Q

What are the two types of retinoblastoma?

A

Sporadic and Familial

32
Q

What is sporadic retinoblastoma?

A
  • Approx 60% of Rb cases
  • No family history
  • Single tumour
  • Unilateral
33
Q

What is familial retinoblastoma?

A
  • Approx 30% of Rb cases
  • Family history
  • Multiple tumours
  • Bilateral
  • 500x increased risk of subsequent osterosarcoma/other tumours
34
Q

What are 3 ways that the RB1 gene can be mutated?

A
  1. Mutation or gene deletion
  2. Loss of heterozygosity (part of the chromosome containing the RB1 sequence)
  3. Promoter hypermethylation resulting in inactivation of transcription of RB1

Biology of Cancer (19 decks)

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