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eMCD - Can > Cancer 2: Oncogenes + tumor suppressors > Flashcards

Cancer 2: Oncogenes + tumor suppressors Flashcards

1
Q

What are the 6 main hallmarks of cancer cell phenotype?

A

Cancer cells… :

  • Disregard of signals to stop proliferating.
  • Disregard of signals to differentiate.
  • Has capacity for sustained proliferation.
  • Evades apoptosis.
  • Has ability to invade.
  • Has ability to promote angiogenesis –> as tumor grows there is increase in demand for nutrients
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2
Q

What is the function of proto-oncogenes?

A

Proto-oncogenes code for essential proteins involved in maintenance of cell growth, division and differentiation.

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3
Q

What happens when proto-oncogene becomes mutated?

A

mutation converts proto-oncogene to an oncogene

  • -> a single mutation may be enough for conversion
  • -> protein no longer responds to control influence
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4
Q

What are the different methods of oncogene activation?

A
  1. mutation in coding sequence –> forms aberrantly active protein
  2. gene amplication / multiple gene copies –> causes overproduction of normal protein)
  3. chromosomal translocation
    OR
  4. insertional mutagenesis
    (e.g burkitt’s lymphoma)
    –> strong enhancer can increase normal gene levels
    (e.g philadelphia chromosome)
    –> strong enhancer can form fusion gene

insertional mutagenesis - Viral infection

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5
Q

Proteins involved in signal transduction are potential critical gene targets (proto-oncogenes)

A

look at diagram on slide —

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6
Q

Activation of proto-oncogenes to oncogenes disrupts normal activity

A

??????????????

look at diagram on slide —

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7
Q

How does a mutant RAS form?

A
  • mutant RAS = has aberrant activity
  • GTP binds to RAS –> RAS becomes active
  • Which activates RAF
  • GTP is dephosphorylated to form –> GDP
  • then GDP unbinds from RAS –> and signals to switch RAS off
  • mutant RAS –> fails to dephosphorylate GTP
  • -> so RAF remains active
  • -> increased stimulus to proliferate
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8
Q

What are features of inherited cancer susceptibility?

discovery of Tumor suppressor genes

A
  • Family history of related cancers.
  • early age of onset.
  • Bilateral tumours in paired organs.
    (e. g in kidneys –> other kidney may also be affected)
  • Synchronous / successive tumours.
    (constant development of tumor even after treatment)
  • Tumours in different organ systems of same individual.
  • Mutation = inherited through germline.
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9
Q

What is retinoblastoma?

A

Malignant cancer of developing retinal cells.

  • due to mutation of RB1 Tumor suppressor gene on chr 13q14
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10
Q

unilateral/ bilateral/ multifocal / one eye

Sporadic Retinoblastoma –> usually

Hereditary Retinoblastoma –>

A

Sporadic Retinoblastoma –> usually involves one eye

Hereditary Retinoblastoma –> unilateral/ bilateral + multifocal disease

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11
Q

Why does mutation of RB1 Tumor suppressor gene on chronic 13q14 cause retinoblastoma?

(i.e what does RB1 usually encode for)

A
  • RB1 encodes for nuclear protein involved in regulation of cell cycle
  • mutation –> causes disrupts normal cell cycle
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12
Q

What are some functional classes of tumor suppressor genes?

i.e what are functions of tumor suppressor genes

A
  • Regulate cell proliferation
  • Maintain cellular integrity
  • Regulate cell growth
  • Regulate the cell cycle
  • Nuclear transcription factors
  • DNA repair proteins
  • Cell adhesion molecules
  • Cell death regulators
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13
Q

What is P53 gene?

A

P53 = tumor suppressor gene

  • suppresses action of oncogene
  • -> SPECIAL BECAUSE it requires a single mutational event on a single allele — > to cause problem

(acts like an oncogene )

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14
Q

How does P53 mutation cause tumor?

A
  • P53 mutant –>
  • it is dominant
  • mutation of single copy = enough to get dysregulation of activity
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15
Q

What is APC tumor suppressor gene ?

A

Due to a deletion in 5q21 resulting in loss of APC gene (tumour suppressor gene).

  • takes part in WNT signaling pathway
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16
Q

What does APC protein normally do?

A
  • APC protein –> helps control activity of B-catenin

- thus prevents uncontrolled growth

17
Q

note:
G0 - quiescent phase (not replicating)
G1 - Cell makes sure there is enough nutrients etc. to replicate
G2 - point of reflection

there is a checkpoint at the end of G1 phase

A

-

18
Q

describe the formation of Philadelphia chromosome

A
  • chr 9 + 22
    ABL gene (normally on Chr9) = placed in appropriate position
    next to BCR gene (on Ch22)
    there is a translocation
  • so that new Chr 22 has both ABL + BCR gene
    –> which can drive to form tumor like phenotype
    CML
19
Q

RAS SIGNALLING

in terms of RAS signaling how might RAF be activated to cause characteristic of oncogenes?

A 
ras - on memb  
when it binds to GTP 
RAF associates with RAS 
when GTP = hydrolyses RAF is released 
and signalling stops
  • when bound –> it is signaling to tell cells to divide

damage to RAF –> signal is permanently turned on –> cause constant division of cells

20
Q

mutation of single copy of proto-oncogene –> oncogene

A

drives the cancer process

21
Q

SRC gene is usually linked to cancer of ….

state its main mechanism

A

Breast/ lung /colon

via over expression/ C terminal deletion

22
Q

note:
- proto oncogene - 1 damage –> dominant

  • tumor suppressor genes –> needs both genes to be damaged to have tumor like effects
A

-

23
Q

How would you treat retinoblastoma ?

A

remove affected eye

  • but likely that retinoblastoma will also affect other eye
24
Q

What is BRCA 1 gene?

A
  • it is a tumor suppressor gene

- mutation = responsible for breast/ ovarian/ prostate cancer

25
Q

What might cause MDM2 to release P53?

how does P53 normally work?

A
  • e.g oncogene activation/ hypoxia / oxidative stress / Double strand breaks

P53 is released dimerizes –> to form functional unit
- regulates P53 target gene –> to act against moderately stress
OR
- undergoes protein protein interactions –> to induce apoptosis

26
Q

What is the APC tumor suppresser gene normally involved in?

what happens when APC TSG is mutated ?

A

APC - involved in cell adhesion + cell signaling normally

mutation –> FAP

  • lots of polyps in colons
  • 90% risk of colorectal carcinoma
27
Q

development of colorectal cancer

A
  • look at diagram / time graph -
28
Q

compare between oncogenes VS Tumour supressor genes

A

ONCOGENE

  1. Gene active in tumour
  2. Specific translocations/point mutations
  3. Mutations rarely hereditory
  4. Dominant at cell level
  5. Broad tissue specificity
  6. more associated with Leukaemia and lymphoma

TUMOUR SUPPRESSOR GENE

  1. Gene inactive in tumour
  2. Deletions or mutations
  3. Mutations can be inherited
  4. Recessive at cell level
  5. Considerable tumour specificity
  6. more associated with Solid tumours
29
Q

Why is cell cycle important in cancer?

A
  • Cycle checkpoints (growth arrest ensures genetic fidelity).
  • Specific proteins accumulate/ destroyed during cycle:
    o E.g. Cyclins, CDKs, CKIs
  • cell cycle Complexes phosphorylate/activate proteins or transcription factors at specific points
  • Permanent activation of a cyclin can drive cell through checkpoint uncontrolled
30
Q

What is meant by insertional mutagenesis?

A

insertion of inappropriate DNA into wrong spot in genome –> which can form chimeric gene

31
Q

APC = another TSG

A
  • Loss of APC gene
    –> causes familial adenomatous polyposis (FAP) –>
    many polyps –> increased risk of colon cancer

–> predisposes colonic epithelial cells to hyperproliferative state.

32
Q
  • APC participates in ____ signalling pathway.
A
  • APC participates in WNT signalling pathway.
33
Q

How can APC / FAP mutation be treated?

A

o Treat by removal of colon to lower cancer risk

eMCD - Can (15 decks)

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