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MCD Cancer > Oncogenes and Tumour Suppressor Genes > Flashcards

Oncogenes and Tumour Suppressor Genes Flashcards

1
Q

what are the 6 hallmarks of cancer?

A 
o	Disregard signals to stop proliferating.
o	Disregard signals to differentiate.
o	Capacity for sustained proliferation.
o	Evasion of apoptosis.
o	Ability to invade.
o	Ability to promote angiogenesis.
\+ avoid immune destruction 
\+ tumour promoting inflammation 
\+ genome instability and mutation
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2
Q

what ensure genetic fidelity?

A

Cycle checkpoints

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3
Q

what do proto-oncogenes code for?

A

essential proteins involved in maintenance of cell growth, division and differentiation.

produce normal protein, expressed normally and respond to signals appropriately

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4
Q

what does a mutated proto-oncogene produce?

A

oncogene (whose protein product does NOT respond to control influences)

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5
Q

how can oncogenes be active?

A

be aberrantly expressed, over-expressed or aberrantly active

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6
Q

what is the minimal requirement for a proto-oncogene to become an Oncogene?

A

can be converted to an oncogene by A SINGLE MUTATION.

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7
Q

what are the 4 ways a normal proto-oncogene can become an oncogene?

A
  1. Mutation in the coding sequence
    - leading to an aberrant protein
  2. Gene amplification
    - leading to overproduction of the normal protein
  3. Chromosomal translocation e.g chimeric genes
    - enhancer added to increase normal protein levels
  4. Insertional mutagenesis e. g viral infection
    - fusion protein created is hyperactive
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8
Q

what are the mutations that can occur in a coding sequence?

A

Point mutation or deletion.

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9
Q

what happens in gene amplification?

A

A protein may block the DNA polymerase so the polymerase repeatedly backs up to go over the area a few times creating many identical genes.

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10
Q

what genes are produced in chromosomal translocation?

A

Chimeric genes.

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11
Q

example of gene created by chromosomal translocation?

A

Philadelphia chromosome (translocation between Chr 9 and 22)

Bcr-abl encodes a tyrosine kinase receptor that does not switch off which is anti-apoptotic enable cancer cell survival

leads to CML

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12
Q

what is insertional mutagenises?

A

Viral infections – some viruses insert their genome into our DNA and usually this isn’t a problem as much of our DNA does not code but if it’s in a coding region, this could be cancer.

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13
Q

examples of proto-oncogenes and proteins they produce?

A

o Tyrosine kinase receptors EC – met, neu.
o Tyrosine kinase receptors IC – src, ret.
o Transcription factors – myc, fos, jun.
o GPCR g-proteins – ras, gip-2.
o Kinases – raf, pim-1.

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14
Q

how is Ras switched on and switched off?

A

binding GTP, RAS becomes active and it’s dephosphorylation of GTP to GDP switches RAS off.

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15
Q

what does Ras binding to GTP enable?

A

allows RAS to bind RAF and pass the signal to RAF deliver the signal further to MEK and ERK.
Dephosphorylation unbinds Raf from Ras

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16
Q

what does mutant Ras do?

A

fails to dephosphorylate GTP and remains active and bound to RAF and drives proliferation.

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17
Q

what is the cancer associated with Myc transcription factor?

A

a translocation can lead to Burkitt’s lymphoma

18
Q

what is the cancer associated with ha-ras and ki-ras g proteins?

A

a point mutation can lead to bladder and colon&lung cancer respectively

19
Q

what are tumour suppressor genes (TSGs)?

A

encode proteins whose function is to regulate cellular proliferation and maintain cell integrity
– e.g. pRb.

20
Q

how many copies of each TSG is present in cells? how many mutations are required to drive cancer?

A

Each cell has 2 copies of each TSG

mutation/deletion of 1 copy is (usually) insufficient to promote cancer
mutation or loss of BOTH copies means a loss of control.

21
Q

what are common features of susceptibility to cancers due to TSG mutations?

A
  • Family history
  • Early age of onset
  • Bilateral tumours in paired organs (seen with non-sporadic retinablastomas for example)
  • Synchronous/successive tumours
  • Different organ tumours in the same individual
  • Mutation inherited through germline
22
Q

what hypothesis describes the activation of cancer via TSGs?

A

Knudson’s 2 hit hypothesis

23
Q

what is the difference between sporadic and inherited cancers due to TSGs?

A

sporadic–> 2 acquired mutations of TSGs (rare)

inherited –> 1 acquired mutation and 1 inherited mutation (more common)

24
Q

what causes retinoblastoma?

A

Malignant cells of developing retinal ganglionic cells.
o Mutation of RB1 (retinoblastoma) TSG on Chr 13q14.
o RB1 encodes a nuclear regulation protein:retinoblastoma protein
- requires two mutated copies

treatment is to remove the eye

25
Q

what are the sporadic and inherited differences in the presentation of retinoblastoma?

A

A sporadic disease usually involving one eye.

The hereditary versions can be uni/bilateral or multifocal (multiple tumours).

26
Q

what are the functional classes of TSGs?

A
  • Regulate cell proliferation
  • Maintain cellular integrity
  • Regulate cell growth.
  • Regulate cell cycle
  • Nuclear transcription factors
  • DNA repair proteins.
  • Cell adhesion molecules
  • Cell death regulators.

these suppress the neoplastic phenotype of a cell

27
Q

what is the associated cancer with p53 regulator mutation?

A

colon
breast
lung

28
Q

what is the associated cancer with BRCA1 regulator mutation?

A

breast
ovarian
prostate

29
Q

what is the associated cancer with PTEN (phosphates) mutation?

A

prostate

glioblastoma

30
Q

how is p53 TSG mutation different in cancer activation?

A
  • mutation of a SINGLE copy is enough to cause dysregulation of activity and cancer.
    (normally TSGs requires mutations on both alleles)
  • Mutant p53 produces a protein that acts in a dominant manner
  • one of the most common defects in cancer
31
Q

what keeps p53 in inactive state? when does it become active?

A

MDM2 keeps p53 in an inactive state
under stress p53 disassociates from
MDM2 and becomes active by forming p53 tetramer

32
Q

what is the effect of APC TSG deletion at 5q21?

A

Familial adenomatous polyposis coli

hyperproliferation in colon

33
Q

what is APC involved in? i.e what is its role

A

in cell adhesion and signalling

34
Q

what is the risk associated with multiple benign adenomatous polys in the colon due to APC loss?

A

90% risk of colorectal carcinoma.

35
Q

what pathway is APC involved in? what does this control?

A
  • WNT signalling pathway
  • control activity of beta-catenin (degrades it)
  • prevents uncontrolled cell growth.

beta catenin involved in cell-cell adhesion and gene expression. Binds to cadherins to form cell-cell adhesions

36
Q

what are the 3 combinations of genes that trigger cancer?

A

o Oncogene + TSG.
o Proto-oncogene + defective TSG.
o Oncogene + defective TSG.

37
Q

what is the pathway to colorectal cancer?

A

1) epithelium
2) APC–> hyperproliferation
3) K-ras (+ DNA hypomethylation) –> adenoma
4) p53–> carcinoma
5) metastasis

38
Q

oncogene summary

A
  • gene is activated
  • occurs as specific translocations/point mutations
  • rarely hereditary
  • dominant
  • broad tissue specificity
  • in leukaemia and lymphomas
39
Q

tumour suppressor gene summary

A
  • gene is inactivated
  • occurs as deletion or mutations
  • can be inherited
  • recessive
  • considerable tumour specificity
  • solid tumours
40
Q

which defective gene, oncogene or TSG defect , is more likely to be inherited?

A

TSG defect

  • inherited in the germline
  • show early onset

MCD Cancer (17 decks)

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