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MD2002 > Molecular Pathology of Tumours > Flashcards

Molecular Pathology of Tumours Flashcards

1
Q

what are properties of malignant cells?

A
  • disordered proliferation
  • disordered apoptosis
  • disordered differentiation
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2
Q

what is dysplasia?

A
  • abnormal growth and differentiation
  • the presence of cells of an abnormal type within a tissue, which may signify a stage preceding the development of cancer
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3
Q

what sort of genes become altered in tumours?

A
  • oncogene activation

- tumour suppressor gene inactivation

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4
Q

oncogenes

A
  • drivers of neoplastic behaviour
  • proto-oncogene
  • dominant mutation (gain of function)
  • single mutation event in proto-oncogene creates oncogene

(neoplastic: abnormal proliferation which persists even after stimulus is withdrawn)

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5
Q

what can oncogenes affect?

A
  • growth factor: sis (platelet derived growth factor, PDGF), fibrosarcoma
  • growth factor receptor: HER2, breast cancer
  • signal transducer: ras, colon cancer
  • transcription factor: myc, Burkitt’s lymphoma
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6
Q

tumour suppressor genes

A
  • recessive mutation (loss of function)
  • needs second mutation event to inactivate second gene copy
  • two inactivating mutations functionally eliminates the tumour suppressor gene, stimulating cell survival and proliferation
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7
Q

gatekeeper genes

A
  • inhibit proliferation or promote death of cells, especially those with DNA damage
  • send negative signals to the cell
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8
Q

caretaker genes

A
  • maintain integrity of the genome by promoting DNA repair
  • nucleotide excision repair
  • mismatch repair
  • DNA double strand break repair
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9
Q

p53

A
  • gatekeeper and caretaker functions
  • most frequently mutated gene in cancerous mutations
  • guardian of genome
  • stops cell cycle so that DNA repair can happen or direct cells towards death if damage too severe
  • activates genes whose products implement these effects
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10
Q

normal p53 function

A
  • apoptotic cell death

- mutation repaired

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11
Q

abnormal p53 function

A

tumour

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12
Q

gene amplification

A
  • normal protein greatly overproduced
  • over expressed growth factors
  • breast cancer
  • Her2 targeted with drug, Herceptin
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13
Q

chromosome rearrangement

A

translocation:
1. nearby regulatory DNA sequence causes normal protein to be overproduced
OR
2. fusion to actively transcribed gene produces hyperactive fusion protein

  • philadelphia chromosome in leukaemia
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14
Q

chromosome rearrangement

A

translocation:
1. nearby regulatory DNA sequence causes normal protein to be overproduced
OR
2. fusion to actively transcribed gene produces hyperactive fusion protein

  • philadelphia chromosome in leukaemia
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15
Q

how do oncogenes work?

A

a) direct stimulation of cell cycle dependent transcription - myc
b) increased/activation of growth factor receptors - HER2
c) increased growth factor - sis
d) interference with intracellular signalling - ras

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16
Q

how do oncogenes work?

A

a) direct stimulation of cell cycle dependent transcription - myc
b) increased/activation of growth factor receptors - HER2
c) increased growth factor - sis
d) interference with intracellular signalling - ras

17
Q

retinoblastoma

A
  • 2/3 cases sporadic (one eye affected)
  • 1/3 bilateral
  • bilateral average diagnosis is 9 months old
  • unilateral average diagnosis 2.5-3 y/o
  • approx. 40 cases/year in UK
  • survival rate: 95-98%
18
Q

retinoblastoma

A
  • 2/3 cases sporadic (one eye affected)
  • 1/3 bilateral
  • bilateral average diagnosis is 9 months old
  • unilateral average diagnosis 2.5-3 y/o
  • approx. 40 cases/year in UK
  • survival rate: 95-98%
19
Q

Rb gene normal activity

A
  • inhibits proliferation
  • represses action of E2F, a transcription factor required to transcribe genes such as DNA polymerase required for entry into S phase
20
Q

Rb gene + phosphorylation

A
  • Rb becomes inactivated by phosphorylation
  • repression is relieved and cells can move into S phase
  • in tumours Rb is inactivated so there can be expression of S phase genes and cell driven towards proliferation even when it wouldn’t normally do so
21
Q

Rb gene + phosphorylation

A
  • Rb becomes inactivated by phosphorylation
  • repression is relieved and cells can move into S phase
  • in tumours Rb is inactivated so there can be expression of S phase genes and cell driven towards proliferation even when it wouldn’t normally do so
22
Q

gatekeeper genes: APC and FAP

A

APC (adenomatous polyposis coli): keeps level of transcription of genes required for proliferation very low

Mutated in FAP (familial adenomatous polyposis) and about 80% of sporadic colon cancers

23
Q

example of nucleotide excision

A

xeroderma pigmentosa: excision mis-formed bases e.g. following UV thymine dimers

24
Q

example of mismatch

A

hereditary non-polyposis colon cancer HNPCC

25
Q

example of DNA double strand break

A

BRCA1-linked hereditary breast and ovarian cancer

26
Q

nature of p53 mutations

A
  • missense mutations
  • transcription factor i.e. binds DNA at particular sequences and activates transcription of genes with those sequences
  • most mutations are loss of function mutations and prevent DNA binding
27
Q

BCL2

A
  • normally inhibits cell death pathway

- BCL2 oncogene: over-expression results in increased cell survival, decreased cell death

28
Q

polyps

A

pre-malignant lesions

29
Q

telomerase

A
  • highly expressed in embryonic stem cells and cells that are dividing rapidly
  • low level expression in most somatic cells
  • loss of telomeres associated with ageing
30
Q

tumours >0.2mm

A
  • to survive must have blood supply
  • VEGF = vascular endothelial growth factor
  • expression triggered by low oxygen
31
Q

invasion and metastasis steps

A
  1. escape from parent tissue:
    - invasiveness causes entry into vessel
  2. travel through circulation:
    - survival in circulation
    - arrest in capillary or other small vessel
    - exit into remote tissue or organ
  3. colonisation of remote site
    - survival of cells in foreign tissue
    - initial growth of cells in foreign tissue
    - persistence of growth
32
Q

‘7 deadly sins’ of tumours

A
  1. self sufficiency in growth signals
  2. insensitivity to growth-inhibitory signals
  3. invasion of apoptosis
  4. defects in DNA repair
  5. limitless replicative potential
  6. sustained angiogenesis
  7. ability to invade and metastasise

MD2002 (85 decks)

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