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path2220 > 14 - Molecular basis of Cancer > Flashcards

14 - Molecular basis of Cancer Flashcards

1
Q

How is a tumour formed

A

By the clonal expansion of a single precursor cell that has incurred genetic damage

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2
Q

4 classes of genes that are the main ‘targets’ for ongogenic mutations

A
  • Proto-oncogenes
  • Tumour suppressor genes
  • Apoptosis regulating genes
  • DNA repair genes
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3
Q

Proto-oncogenes

A

normal cellular genes whose products promote cell proliferation (growth factors, signal transducers, transcription factors)

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4
Q

Tumour supressor genes

A

mutations are usually “loss of function”, so both copies need to be affected

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5
Q

DNA repair genes

A
  • Impair the ability of the cell to repair DNA damage
  • Thus more mutations are acquired: “mutator phenotype”
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6
Q

Driver mutations

A

Mutations that contribute to the development of the malignant phenotype

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7
Q

What does cancer formation result from

A

The accumulation of mutations in a stepwise fashion over time

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8
Q

Passenger mutations

A

Mutations that may have no phenotypic consequence (loss of function mutations are common early step)

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9
Q

How do tumours evolve

A
  • Under Darwinian selection
  • Emergence of subclones within the tumour
  • Leads to therapy resistance
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10
Q

Epigenetic modifications

A

Inheritable modifications of DNA which is not related to a coding change (e.g. DNA methylation, histone modification)

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11
Q

Oncogenes

A

mutated or over-expressed versions of proto-oncogenes that function autonomously, having lost dependence on normal growth promoting signals

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12
Q

Oncoprotein

A

a protein encoded by an oncogene that drives increased cell proliferation through several mechanisms

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13
Q

Mechanisms of Oncoproteins

A
  • Constitutive expression of growth factors and their
    receptors, setting up an autocrine cell signalling loop
  • Activation of signal transduction molecules
  • Activation of transcription factors
  • Increase the activity of CDK4)
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14
Q

ERBB1

A
  • Encodes the epidermal growth factor receptor (EGFR)
  • Point mutations result in constitutive activation of the tyrosine kinase
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15
Q

ERBB2

A
  • Encodes receptor tyrosine kinase HER2
  • Amplified in some breast cancers, leading to overexpression of the HER2 receptor
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16
Q

ALK

A
  • Receptor tyrosine kinase on chromosome 5
  • In some lung cancers a fusion of EML4-ALK results in a chimeric EML4-ALK protein with constitutive kinase activity
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17
Q

effects of a mutated MYC gene

A
  • Activates the expression of genes involved in cell growth
  • Upregulates telomerase expression
  • Reprograms somatic cells into a stem cell-like phenotype
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18
Q

Tumour suppressor genes

A
  • Act as a ‘brake’
  • Abnormalities of these genes lead to failure of growth inhibition
  • Form a network of checkpoints which prevent
    uncontrolled growth
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19
Q

How do tumour suppressor genes prevent uncontrolled growth

A
  • Shut down proliferation
  • Initiate apoptosis
  • Promote differentiation
20
Q

Retinoblastoma (RB) Gene

A
  • Directly or indirectly inactivated in most human cancers
  • A key negative regulator of the G1/S cell cycle transition
21
Q

Hypophosphorylated RB gene

A
  • RB exerts antiproliferative effects by binding and inhibiting E2F transcription factors
  • Growth factor signalling leads to RB hyperphosphorylation and activation
22
Q

In cancer, how can RB function be compromised

A
  • Loss of function mutations in RB
  • Loss of function of CDK inhibitors
  • Gain of function of CDK4 and cyclin D
  • Viral oncoproteins that bind and inhibit RB
23
Q

Retinoblastoma tumour

A
  • An intraocular malignancy of children
  • Can be familial (autosomal dominant, bilateral) or sporadic (unilateral)
24
Q

TP53

A
  • Tumour suppressor gene
  • Mutations are acquired in both alleles in somatic cells
  • Inheritance leads to a predisposition of “Li-Fraumeni syndrome”
25
Q

p53 in non stressed cells

A

p53 is degraded via an
association with MDM2

26
Q

p53 in stressed cells

A

p53 is released from this
inhibition and accumulates

27
Q

CDKN2A

A

Loss of function impacts both RB and p53 tumour suppressing pathways

28
Q

p16/INK4a

A

Blocks CDK4/cyclin D mediated phosphorylation of RB, reinforcing the RB checkpoint

29
Q

p14/ARF

A

Activates p53 by inhibiting
MDM2 and stabilising p53

30
Q

Apoptosis

A
  • Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program in which cells activate caspases that degrade the DNA and proteins
  • Protective response to
    conditions which may result in cancer
31
Q

Are mutations in DNA repair genes oncogenic

A

No, but enhance the occurrence of other mutations which might be

32
Q

DNA mismatch repair

A
  • Correct single base errors (GT pairing rather than AT)
  • Inheritance of one mutant copy results in Familial carcinomas of the colon
  • These tumours are characterised by microsatellite instability
33
Q

Microsatellites

A
  • Tandem repeats of 1-6 nucleotides found throughout the genome
  • Length remains constant
  • With loss of mismatch repair these satellites increase or decrease
    in length (unstable)
34
Q

Nucleotide Excision Repair

A
  • UV radiation causes cross-linking of pyrimidine residues, preventing normal DNA replication (pyrimidine dimers)
  • Repaired by NER
  • Inherited loss of one of the genes involved in this system leads to increased risk of developing skin cancers
35
Q

Homologous recombination

A
  • Defects in the homologous recombination cause group of disorders characterised by hypersensitivity to DNA damaging agents
  • Mutations in BRCA1 or 2 account for 25% of familial breast cancer
  • Cells with these mutations develop chromosomal breaks and abnormal numbers of chromosome
36
Q

Hereditary Leiomyomatosis and Renal Cell Cancer

A
  • develop multiple smooth muscle tumours (leiomyomas) in the skin and uterus, as well as aggressive renal cell carcinomas
  • Caused by mutation in Fumarate hydratase
37
Q

Fumarate hydratase

A
  • Enzyme acting
    within the Krebs cycle
  • catalyses the hydration of fumarate to malate
  • Mutations in Krebs cycle components lead to a decrease in oxidative phosphorylation
38
Q

Warburg effect

A
  • Cancer cells tend to ferment glucose into lactate even in the presence of sufficient oxygen
  • “aerobic glycolysis”
39
Q

Possible explanations for the Warburg effect

A
  • ATP is only an issue when resources are scarce
  • Proliferating cells have other metabolic needs besides ATP (Carbon atoms, Acetyl-CoA, NADPH)
40
Q

Angiogenesis

A
  • Even if a tumour has all of the genetic mutations required for limitless growth, it cannot enlarge to more than 1 or 2mm due to a lack of blood supply
  • Promoting the growth of new blood vessels is critical to the survival of neoplasms
41
Q

Two phases of invasion and metastasis

A
  • Invasion of the extracellular matrix
  • Vascular dissemination
42
Q

Can circulating tumour cells can be identified in patients without clinically overt metastatic disease?

A

Yes

43
Q

Immune response to tumour cells

A
  • Tumour antigens are presented on the cell surface
    by MHC class I molecules and are recognised by cytotoxic T-lymphocytes.
  • Immunosuppressed patients have an increased risk for development of cancer, particularly types caused by oncogenic DNA viruses.
44
Q

Mechanisms of evasion of immune defences

A
  • Selective outgrowth of antigen-negative variants
  • Loss or reduced expression of histocompatibility antigens
  • Expression of certain inhibitory factors by the tumour cells, which act to dampen the immune response
45
Q
A

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