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Medicine Year 1 - Semester 2 - Part 2 > Molecular Pathology of Tumours > Flashcards

Molecular Pathology of Tumours Flashcards

1
Q

What is a property unique to a malignant cell ?

A

Ability to spread to other parts of the body.

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2
Q

State some properties of malignant cells

A

Disordered:

  • Proliferation
  • Apoptosis
  • Differentiation
  • Relationship between proliferating cells and surrounding environment
    (invasion, metastasis, angiogenesis)
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3
Q

Describe the multi-step process of tumour formation

A

Normal
Dysplasia
Carcinoma in situ
Invasion (basement membrane is broken)
Metastases

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4
Q

Describe tumour formation - clonality

A

A mutation gives one cell an advantage

A second mutation increases the advantage.

A third mutation increases the advantage further and makes the cell invasive.

Dangerous cell survival, proliferation and invasion.

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5
Q

What sort of genes are altered in mutations ?

A

Oncogene activation

Tumour supressor gene inactivation

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6
Q

What are oncogenes ?

A
  • Drivers of neoplastic behaviour (out of control proliferation)
  • Proto-oncogene
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7
Q

How are oncogenes formed ?

A

A single mutation event in a proto-oncogene creates an oncogene.

The activation of the mutation, enables the oncogene to stimulate cell survival and proliferation.

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8
Q

What type of mutation occurs for proto-oncogenes ?

A

DOMINANT mutation
Activating mutation

Gain of function (excessive cell survival and proliferation)

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9
Q

Give an example of an oncogene

A

RAS

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10
Q

What mechanisms can result in the activation of an oncogene ?

A

Mutation in the coding sequence
Gene amplification
Chromosome Re-arrangement

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11
Q

Describe a mutation in the coding sequence - RAS

A

Can happen in an oncogene like RAS.

Found in colon cancer, where the 12th amino acid of RAS is converted from glycine to valine.

RAS protein becomes locked in an ON position, and is able to send signals down the cascade to tell cells to divide.

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12
Q

Result of a mutation in the coding sequence

A

Hyperactive protein made in normal amounts

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13
Q

Describe gene amplification : HER2

A

HER2- epidermal growth factor

Frequently happens in breast cancer.

Amplification of HER2 gene, which over expresses the protein to a high extent.

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14
Q

Result of gene amplification

A

Normal protein greatly overproduced

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15
Q

Describe chromosome rearrangement : CML (chronic myeloid leukaemia)

A

Rearrangement of Philadelphia chromosome, in order to generate a fusion protein.

BCL gene fused to abl gene.

This produces a hyperactive fusion protein.

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16
Q

Result of chromosome re-arrangement

A

Fusion to actively transcribed gene produces hyperactive fusion protein.

OR

Nearby regulatory DNA sequence causes normal protein to be overproduced.

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17
Q

Functional consequences of oncogenes

What are there mutations in ?

A

Mutations in:

  • Growth factor
  • Growth factor receptor
  • Signal transducer
  • Transcription factor
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18
Q

Growth factor mutations

A

Sis (over expressed gene), Fibrosarcoma

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19
Q

Growth factor receptor mutations

A

HER2, Breast cancer

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20
Q

SIgnal transducer mutations

A

Ras, Colon cancer

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21
Q

Transcription factor mutation

A

Myc, Burkitt’s lymphoma

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22
Q

How do oncogenes work ?

Four ways

A

4 ways:

Direct stimulation of cell cycle dependent transcription.

Increased/activation of growth factor receptors

Increased growth factor

Interference with intracellular signalling

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23
Q

Describe tumour suppressor genes

A

Recessive mutation
LOSS of function mutation

Excessive cell survival and proliferation

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24
Q

Feature of tumour suppressor genes

A

LOSS of function mutations (2 inactivating mutations) functionally eliminates the tumour suppressor gene, stimulating cell survival and proliferation.

25
Q

Retinoblastoma: Knudson’s 2 hit hypothesis

A

Normally paired RB1 genes
Mutational loss of one RB1 gene

Mutational loss of the other RB1 gene in the same cell/ its daughter cell.

This may lead to 1 eye with retinoblastoma. Other eye with none of these cells - normal.

Inherited absence of 1 of the paired RB1 genes.

Mutational loss of RB1 in any retinal cell

High risk of bilateral retinoblastoma

26
Q

Bilateral retinoblastoma

A

Inherited retinoblastoma

Only need 1 mutation
Earlier age of onset

27
Q

Unilateral retinoblastoma

A

Sporadic retinoblastoma

Needs 2 mutations to occur

28
Q

Normal function of RB1

A

A transcription factor, which sits on top of other transcription factors and prevents the expression of genes, which are required for DNA synthesis.

29
Q

Why does mutating RB drive carcinogenesis ?

A

Non-proliferating cell.

Inactive Rb, in an uncontrolled way (mutated).

We can activate transcription and expression of S-phase genes are activated.

30
Q

State the 2 types of tumour suppressor genes

A

Gatekeepers
Caretakers

31
Q

Gatekeeper - tumour suppressor genes

A

Inhibit proliferation or promote the death of cells, especially those with DNA damage.

Sends negative signals to the cell.

32
Q

Example of a tumour suppressor gene mutation - gatekeeper

A

Familial adenomatous polyposis coli

Retinoblastoma

33
Q

Describe caretaker - tumour supressor genes

A

Maintain the integrity of the genome by promoting DNA repair.

  • Nucleotide expansion repair
  • Mismatch repair
  • DNA double strand break repair
34
Q

Examples of tumour suppressor gene mutations - caretaker type

A

Xeroderma Pigmentosa

Hereditary non-polyposis colon cancer

Breast & Ovarian Cancer

35
Q

State a tumour suppressor genes that is both a caretaker and a gatekeeper

A

p53

p53 is widely mutated in a wide range of different tumours

36
Q

p53

A

tumour suppressor gene

37
Q

Li-Fraumeni family

A

Inherited mutation in p53

Predisposes them to a wide variety of cancers.

38
Q

What is a missense mutation ?

A

Amino acid substitution

39
Q

Result of a mutation in the p53 gene

A

Loss of function
(normal function is tumour suppressor)

40
Q

Nature of p53 mutations

A

Sequence specific DNA binding

41
Q

What does p53 do ?

Four things

A

Stimulates:

  • Cell cycle arrest
  • DNA repair
  • Block of angiogenesis
  • Apoptosis
42
Q

What activates p53 ?

A

Cell damage

  • UV radiation
  • Lack of nucleotides
  • Hypoxia
  • Blockage of transcription
43
Q

Describe homeostatic / normal situations

A

Normal cell division
Normal apoptosis

44
Q

Describe tumour formation situations

A

IN some either:

  • Increased cell division / normal apoptosis
  • Normal cell division / decreased apoptosis
45
Q

BCL2

A

Anti-apoptotic

Inhibits cell death pathway

46
Q

Importance of BCL2

A

IN some instances, the genetics around BCL2 can be re-arranged as part of chromosome translocation.

The wrong promotor can end up in front of BCL2, meaning BCL2 is over expressed.

This results in lymphoma.
(increased cell survival, decreased cell death)

47
Q

Key feature of tumour

A

Limitless replicative potential

Telomerase can be active is tumours - associated with the worst prognosis

47
Q

Multi-Step model of carcinogenesis

A

Normal epithelium
(tumour supressor gene (APC) lost)

Excessive epithelial proliferation
(Oncogene (Ras) activated)

Small tumour
(Another tumour suppressor gene lost)

Large tumour
(A 3rd tumour supressor gene (p53) lost)

Tumour becomes invasive
(rapid accumulation of mutations)

Metastasis

48
Q

How can DNA be damaged ?

A

Chemicals
Radiation
Viruses

49
Q

Describe a chromosome

A

Ends of the chromosome (telomeric DNA)

Body of chromosomal DNA

ENDS - repeated many times to protect the ends of the chromosome and make sure it always remains a standard length.

49
Q

Angiogenesis Signalling Cascade

A

Cancer cell

VEGF - vascular endothelial growth factor

This factor sends a signal to endothelial cells stimulating growth of new blood vessels.

50
Q

Telomerase function

A

Recognises the telomeric DNA and maintains it at ideal lengths.

51
Q

When is telomerase expressed ?

A

Telomerase is highly expressed in dividing cells.

In differentiated, somatic cells, telomerase is no longer expressed.

So as cells undergo successive divisions, there becomes a crisis point where telomere DNA is so short that the chromosome becomes unstable.

52
Q

Endothelial cell activation

A

Activated endothelial cells

Secretes MMPs that digest surrounding matrix

Cell migrates and divides

53
Q

How do tumour cells go from being in a benign state to metastatic state ?

A

Cells grow as a being tumour in the epithelium.

Cells become invasive, break through basement membrane and enter the capillary.

They adhere to the blood vessel wall.

Escape from the blood vessel to find a new home.

Colonise that new home.

54
Q

Changes that occur leading to metastases

A

Tumour cells detach from each other because of reduced adhesiveness.

Cells then attach to the basement membrane via the laminin receptors.

Cells secrete proteolytic enzymes, including type IV collegenase and plasminogen activator.

Degradation of the basement membrane and tumour cell migration follow.

55
Q

Easy stage of invasion and metastasis

A

Travel through circulation

56
Q

Difficult stages of invasion and metastases

A

Escape from parent tissue
Colonisation of remote site

57
Q

‘7 deadly sins’ of tumour cells

A

Self-sufficiency in growth signals

Insensitivity to growth-inhibitory signals

Evasion of apoptosis

Defects in DNA repair

Limitless replicative potential

Sustained angiogenesis

Ability to invade and metastasise.

Medicine Year 1 - Semester 2 - Part 2 (53 decks)

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