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B33CAN > Biology 4 - Cancers are Genetic Diseases II (Keith Spriggs) > Flashcards

Biology 4 - Cancers are Genetic Diseases II (Keith Spriggs) Flashcards

1
Q

What causes cancer?

A

Abnormal proliferation and survival of cells as a result of changes in gene expression and gene function.

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2
Q

What is the difference between genetic and inherited?

A

Cancers are genetic; mutations normally arise in somatic cells - for a cancer to be inherited the mutation would have to arise in a gamete.

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3
Q

How many mutations are needed in order for them to have an effect?

A

Atleast two mutations are necessary to initiate cancer e.g. a RAS-like oncogene (cytoplasmic) and an MYC-like oncogene (nuclear).

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4
Q

On average, how many mutations are needed in order to cause cancer in adults?

A

4 or 5

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5
Q

How can cancerous mutations be described as a ‘vicious circle’?

A

> 100 genes in a cell contribute to DNA repair
If one of these was to mutate then it could predispose to a higher mutation rate allowing further tumour progression.
Without genes that are able to repair DNA then the chromosome can become unstable. (Fusion, breaking, instability)

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6
Q

What changes to genetic information can have profound effect on the cell behaviour?

A

Gene amplification, deletion, chromosome rearrangements, small mutations at critical sites.

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7
Q

What is p53?

A

A transcription factor

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8
Q

What is the most mutated gene is human cancers?

A

TP53

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9
Q

What is a hotspot residue? Give an example

A

A residue that, if mutated, is more likely to lead to cancer. In TP53, R175 is a hotspot residue.

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10
Q

What happens in a ‘loss of function’ mutation in p53?

A

Loses its function as a tumour supressor

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11
Q

What happens in a ‘gain in function’ mutation of p53?

A

Gains oncogene activity - it does this by antagonising unmutated p53 function by aberrant binding to DNA or proteins.
STOPS normal functioning p53.

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12
Q

What is INK4?

A

INK4 is a family of cyclin-dependent kinase inhibitors (CKIs).

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13
Q

What is the role of INK4?

A

Inhibit cyclin-dependent kinase

  • Prevent cell cycle progression
  • Prevent Rb phosphorylation
  • Tumour suppressor
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14
Q

What happens to INK4 in cancers?

A

INK4 deletion

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15
Q

What is p16?

A

Part of the INK4 family of cyclin-dependent kinase inhibitors - it is a tumor suppressor protein

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16
Q

What gene is amplified in approximately 7% of all cancers?

A

MDM2 amplification

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17
Q

What is the consequence (balance) of more MDM2 when it is amplified in cancer?

A

Less p53 because MDM2 adds ubiquitin (small regulatory protein) to p53.
Errors in DNA replication and repair lead to the copying of a gene multiple times.

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18
Q

What genes, as well as MDM2, are commonly amplified in cancer?

A 
MDM2
MYC
RAS
HER2
EGFR
19
Q

What is the premise of the Philadelphia chromosome?

A

Reciprocal translocation of chromosomes 9 and 22

This fuses BRC and Abl.

20
Q

What is BRC?

A

A serine threonine kinase and GTPase

21
Q

What is ABL?

A

A signalling tyrosine kinase

22
Q

What happens after the reciprocal translocation of chromosome 9 and 22 in the Philadelphia chromosome and fusing of BRC and ABL?

A

The fusion protein has TK activity, but is no longer regulated

23
Q

What cancer is the Philadelphia chromosome commonly associated with?

A

Chronic myeloid leukaemia.

24
Q

How can the Philadelphia chromosome treated pharmacogologically?

A

Tyrosine kinase inhibitors

Imatinib, Nilotinib, Dasatinib

25
Q

What can happen to EGFR that can cause cancer?

A

Partial deletion of EGFR
The extracellular portion of the receptor is deleted, this means that the ligand can no longer bind but the domain is constantly active (continuous phosphorylation).

26
Q

What makes EGFR variant III constitutively active?

A

Lacks most of extracellular domain
Variant III has undergone partial deletion and so the remaining segment is within the intracellular domain and remains constantly turned on.

27
Q

What cancer shows a variant (variant III) in 20-60% of glioblastoma multiformes?

A

Variant III after partial deletion of EGFR

28
Q

What sequence is constantly activated as a result of truncated EGFR?

A

RAS –> RAF –> MEK

Switches on approximately 100 genes for cell division

29
Q

What form of mutation can occur in RAS that leads to cancer?

A

Point mutations in RAS affecting codons 12, 13 or 61 leads to constitutively active RAS protein
RAS is a GTPase regulating pathways for proliferation and survival

30
Q

What is RAS?

A

RAS is a GTPase regulating pathways for proliferation and survival

31
Q

What can lead to variation in patient pharmacogenetics?

A 
Drug targets
Metabolising enzymes ( so consequently pro-drug actication)
32
Q

What can be used to predict variation in pharmacogenetics of patients?

A

Gene sequencing

33
Q

What is Tamoxifen metabolised to from pro-drug to active metabolite?

A

CYP2D6 (a cyp450)

34
Q

In patients that do not have the required enzyme to metabolise Tamoxifen into its form, what can be done?

A

CYP2D6 deficient patients

Patients require an increased dose to compensate for reduced active products ( doubling the dose is recommended)

35
Q

What is genetic exceptionalism?

A

Genetic information is not just about a patient at present; it tells us about their future and also about their family (1/2 genetic info shared with offspring and 1/4 with siblings).

36
Q

What are the ethical dilemmas associated with genetic testing / sequencing?

A

Predicts genetic dispositions
Impact on family members
Significance may not be apparent at the time of collection
May have cultural significance
Can be obtained from any cell (even if separate from body)
Potential for abuse

+Scientific research value (-)

37
Q

How do acquired mutations affect treatment type?

A

Tumour genomes can be sequenced in order to personalise treatment (not yet routine but as cost reduces and use becomes more widespread it may become standard)

38
Q

Give some examples of when genome of tumours allows personalised medicine;

A

HER2 for Herceptin
EGFR for Erlotinib, Cetuximab
Uses for monoclonal antibodies

39
Q

What kind of oncogenic mutations can cause cancer?

A 
Chromatin modifications 
Transcription control
Splicing control
microRNA
Translation
Post-translational modifications
40
Q

Which oncogenes can be activated by changes to genetic code?

A

RAS, MDM2, EGFR, (TP53 - inactivates functional p53)

41
Q

Which tumour supressors can be inactivated by mutation?

A

TP53, INK4

42
Q

Give an example of chromosomal rearrangement

A

9 and 22 The Philadelphia Chromosome

BRC and ABL

43
Q

What are DTC genetic tests?

A

Direct to consumer

B33CAN (25 decks)

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