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L3 Clinical Genomics > Hallmarks of cancer > Flashcards

Hallmarks of cancer Flashcards

1
Q

What are the 6 hallmarks of cancer?

A
  • Sustained proliferative signalling
  • Evade growth suppression signals
  • Resist apoptosis
  • Activate invasion and metastasis
  • Enable replicative immortality
  • Induce angiogenesis
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2
Q

How many individuals are affected by new cases of cancer?

A

450 per 100 000

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3
Q

What is the mortality rate associated with new cases of cancer?

A

160 per 100 000

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4
Q

How do cancer cells achieve sustained proliferative signalling? (4)

A
  • Upregulate and release their own mitogenic signalling molecules
  • Stimulate neighbouring tissues to release growth factors
  • Become more sensitive to growth factors to rapidly proliferate in the presence of normal mitogenic signalling
  • Mutations can cause constitutive activation of growth factor-activated signal transduction
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5
Q

What is an example of sustained proliferative signalling? (2)

A
  • Upregulation and overexpression of Her2 on breast cancer cells caused by HER2 gene amplification
  • Gives cancer cells greater sensitivity to Human Epidermal Growth Factor
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6
Q

What is Her2? (2)

A
  • Human Epidermal Growth Factor Receptor
  • Receptor tyrosine kinase which signals via Ras to cause cell cycle progression, proliferation and enhanced survival
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7
Q

Which chromosome is the HER2 gene located on?

A

Chromosome 17

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8
Q

How is Her2 positive breast cancer treated?

A

Monoclonal antibody Herceptin which binds to Her2 receptor and prevents ligand binding and receptor dimerisation

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9
Q

How is Her2 positive breast cancer diagnosed? (3)

A
  • Amplification status is graded into 4 categories
  • Her2 amplification must be over a certain threshold to be prescribed Herceptin
  • Borderline cases are sent for further cytogenomic analysis by FISH
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10
Q

How do cancer cells evade growth suppressors? (4)

A

Loss of function of tumour suppressor genes via:
- Inactivating mutation
- Transcriptional suppression via methylation of a promoter region
- Deletion via chromosomal abnormality
- Altered expression of tumour suppressor regulators

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11
Q

What are examples of tumour suppressor inactivation in cancer? (3)

A
  • TP53
  • RB
  • Other mechanisms of growth suppression evasion include loss of cell-cell contact inhibition
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12
Q

How does RB work? (3)

A
  • RB = retinoblastoma
  • RB function is impaired in most cancers
  • RB forms a complex with E2F which downregulates transcription of genes involved in cell cycle progression
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13
Q

What are the 2 groups of apoptotic regulators?

A
  • Process extracellular signals (extrinsic pathway)
  • Process intracellular signals (intrinsic pathway)
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14
Q

What are apoptotic regulators?

A

Genes involved in sensing apoptotic signals

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15
Q

What are apoptotic triggers?

A

Genes that convey signals from the regulators to the apoptotic effectors

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16
Q

What are the 2 groups of apoptotic triggers?

A
  • Pro-apoptotic triggers (tumour suppressors)
  • Anti-apoptotic triggers (oncogenes)
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17
Q

What is an example of apoptotic triggers?

A

Bcl2 protein family

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18
Q

What is the function of apoptotic triggers?

A

Regulate the apoptotic effectors (caspases)

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19
Q

How often is TP53 mutated in cancer?

A

In around 50% of all cancers

20
Q

What is the function of p53?

A

Promotes cell cycle arrest to allow for DNA repair and/or apoptosis if repair is not possible

21
Q

What is an example of a pro-apoptotic trigger (tumour suppressor)?

A

TP53

22
Q

What is an example of an anti-apoptotic trigger (oncogene)?

A

BCL2

23
Q

What is the prognosis of TP53 loss?

A
  • Poor prognosis
  • Loss of TP53 is a marker of MDS progression into acute myeloid leukaemia
24
Q

How can BCL2 be overactivated in cancer? (2)

A
  • Chromosome structural rearrangement resulting in coupling of BCL2 gene to IGH promoter region resulting in BCL2 overexpression
  • Abnormality is frequently diagnostic of B-cell neoplasms (lymphoma)
25
Q

What are the 2 barriers to replicative immortality?

A
  • Senescence
  • Crisis
26
Q

What is senescence?

A

An irreversible non-proliferative state which is entered when telomeres become too short

27
Q

What are telomeres? (3)

A
  • Protective caps at the end of each chromosome arm consisting of hexanucleotide repeats
  • Maintained by telomerase
  • Shortened in each round of DNA replication, eventually resulting in chromosome fusions (unstable, trigger crisis)
28
Q

What is crisis?

A

Cell death via apoptosis

29
Q

How do cancer cells avoid senescence? (2)

A
  • Activate telomerase expression
  • Upregulate recombination based telomere maintenance mechanisms
30
Q

What makes telomerase an attractive therapeutic target?

A

Near universal association with cancer cells and lack of expression in normal cells

31
Q

What is the problem with telomerase as a therapeutic target? (2)

A
  • Lack of a high-resolution 3D structure makes targeting difficult
  • The impact of inhibition would be slow because would have to wait for successive rounds of telomere shortening before senescence/crisis is triggered
32
Q

Which common diagnostic markers support upregulation of angiogenesis? (2)

A
  • Ras oncogene
  • Myc oncogene
33
Q

Why do cancer cells need to activate angiogenesis?

A

More proliferation = need to sequester more nutrients via the blood to support enhanced metabolism

34
Q

Which molecules involved in normal cell migration are implicated in invasion and metastasis? (2)

A
  • E-cadherin
  • N-cadherin
35
Q

What is the normal action of E-cadherin? (2)

A
  • Assembly of epithelial cell sheets
  • Depleted in metastatic cancers
36
Q

What is the normal action of N-cadherin? (2)

A
  • Expressed in migrating neurons and mesenchymal cells during embryonic development
  • Upregulated in high grade carcinomas
37
Q

What are the steps to metastases formation? (6)

A
  • Local invasion to close-by tissues
  • Entry into blood/lymphatic system
  • Transport through blood/lymphatic system
  • Entry into distant tissues
  • Formation of small cancerous nodes
  • Growth into larger malignant tumour mass
38
Q

What are the emerging hallmarks? (4)

A
  • Deregulation of cellular energetics to support growth and proliferation
  • Genome instability
  • Avoiding immune destruction
  • Promoting inflammation
39
Q

What are 2 important features of tumorigenic behaviour?

A
  • Clonal expansion
  • Clonal evolution
40
Q

What is clonal expansion?

A

Propagation of a particularly competitive cell line within a tumour with advantageous mutations

41
Q

What is clonal evolution?

A

Competitive cell lines are inherently genetically unstable and so are likely to acquire additional abnormalities leading to evolution of the clone

42
Q

What is tumour heterogeneity?

A

Tumours containing multiple sub-populations of cells of different clones competing with eachother

43
Q

Why are mutation rates elevated in cancer cells? (3)

A
  • Increased sensitivity to carcinogens
  • Deregulation of DNA damage sensing and repair pathways
  • Disturbance of chromosome segregation mechanisms
44
Q

What is an example of inherited tumour suppressors?

A

Inheritance of inactivated BRCA1/2 tumour suppressor genes is a risk factor in breast and ovarian cancer

45
Q

What is the function of BRCA1/2 genes?

A

Involved in homologous recombination which is a high fidelity DNA repair pathway for DNA double strand breaks

46
Q

What is the lifetime risk of developing breast cancer with inactivated BRCA1/2 inheritance?

A

50-80%

47
Q

What is the lifetime risk of developing ovarian cancer with inactivated BRCA1/2 inheritance?

A

30-50%

L3 Clinical Genomics (14 decks)

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