5a: Genetic Pathways In Cancer Flashcards

1
Q

Fill in the blanks:
As neoplasia progresses through _____ lesions, the number of mutation acquired by the lesion _____.

A

1) Precursor
2) increases

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2
Q

Fill in the blanks:
Selective advantage ensures that _____ acquisition is broadly _____

A

1) Mutation
2) Consistent

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3
Q

What is oncogene co-operation

A

Where mutations are more likely to be selected based on interactions with previous mutations, allowing oncogenes to co-operate to ensure a positive advtange for the tumour

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4
Q

Which mutation does KRAS often co-occur with?

A

PIK3CA

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5
Q

What is example of two mutations that co-occur in pancreatic cancers but not often in lung?

A

KRAS and TP53

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6
Q

Why may pair of mutations co-occur in one tumour but not another?

A

The context/areas of the tumours are different, therefore co-occurrence may give a select advantage in one but not the other, depending on the tissue types.

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7
Q

Give an example of a mutation that is selected against in endometrial cancers with MSI?

A

TGFRBR2, due to its repeat sequences

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8
Q

Fill in the blanks:

Mutations may select against other mutations.
It is unlikely two mutations will activate the same _____. This will lead to _____ _____.

A

1) Pathway
2 & 3) mutual exclusion

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9
Q

Which 3 mutations are mutually exclusive in the MAPK signalling pathway?

A

EGFR, KRAS, BRAF

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10
Q

Fill in the blanks:
If a mutation is essential, it is an example of oncogene ______.
If a mutation is not essential, it is an example of oncogene ______.

A

1) addiction
2) amnesia

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11
Q

What are the 3 genetic pathways of colorectal cancer?

A
  • Chromosomal instability (CIN)
  • Microsatellite instability (MSI)
  • Chromosome and microsatellite stable
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12
Q

Why is CpG Island Methylator Phenotype colorectal cancer not considered its own genetic pathway despite being well described?

A

Due to its close link to the MSI pathway

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13
Q

Most sporadic CRCs arise as a result of which mutation?

A

APC

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14
Q

Which signalling pathway does APC activate?

A

Wnt signalling

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15
Q

Fill in the blanks:
Approximately __% of sporadic CRC tumours will arise _____ to the _____ _____ (left sided)

A

1) 70
2) distal
3 & 4) splenic flexure

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16
Q

What % of sporadic tumours will show MSI

A

10-15%

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17
Q

When does MSI occur?

A

When there is a failure of the mismatch repair function

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18
Q

What des MSI result in?

A

Hypermutation/ increased mutation rate

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19
Q

What is ‘redundancy’ in regards to the genome?

A

If there is a dysfunctional protein, other similar proteins may act to take over the same role.

20
Q

What are the protein pairs that make up the complex in the DNA mismatch repair pathway?

A
  • MSH2 & MSH6
  • MLH1 & PMS2
21
Q

What causes almost all cases of MSI in sporadic CRC tumours?

A

MLH1 promoter methylation

22
Q

Fill in the blanks:
MSH2/_____ dimers and _____/PMS2 _____ function to excise_____ _____.

A

1) MSH6
2) MLH1
3) dimers
4 & 5) mismatched bases

23
Q

How many of the proteins in the complexes in mismatch repair must be lost in order for the repair to fail?

A

Just 1

24
Q

Will repeats be added/deleted if a loop occurs on the:
- template strand
- newly synthesised strand

A
  • Repeats deleted
  • Repeats added
25
Q

What technology is used to detect microsatellite instability?

A

PCR

26
Q

Fill in the gaps:
Tumours showing MSI and CIN all develop via _____ precursors.
They do represent distinct entities with different _____ and _____.
They may have _____ prognosis and respond differently to ____.

A

1) adenomatous
2 & 3) phenotypes, genotypes
4) different
5) chemotherapy/treatment

27
Q

What is CIN in CRC characterised by?

A

Aneuploidy and allelic loss

28
Q

Which mutations may be responsible for CIN

A

CDC4 and TP53

29
Q

Which genetic pathway in CRC is left/right sided?

A

MSI - right sided
CIN- left sided

30
Q

What are some characteristics of MSI colorectal tumours?

A
  • right sided
  • mucinous
  • have a dense lymphocytic infiltrate
31
Q

Genetically, what is MSI colorectal cancer characterised by?

A
  • Mutations in: TGFBR2, BRAF, BAX
  • Diploid nuclei
  • Lack of TP53 mutations
  • Little allelic loss
32
Q

Which mutations in MSI tumours are mutually exclusive with APC mutations and why?

A

RNF43 and ZNRF3 as they also activate the Wnt signalling pathway

33
Q

Fill in the gaps:
Tumours with MSI have a _____ prognosis (except after _____), they respond better to _____.

A

1) better
2) metastasis
3) immunotherapy

34
Q

What is the consensus molecular subtypes classification related to?

A

Prognosis

35
Q

What do tumours in the CMS1 subtype contain?

A
  • MSI
  • POLE/POLD1 mutations
  • CpG island methylator phenotype
  • immune infiltration/activation
  • hypermutation
36
Q

Using 1 word, how could you describe the 4 CMS groups in colorectal cancer?

A
  • CMS1: MSI immune
  • CMS2: Canonical
  • CMS3: Metabolic
  • CMS4: Mesenchymal
37
Q

What does SCNA stand for

A

Somatic copy number alteration

38
Q

Which CMS group is most distinct from CMS1

A

CMS4

39
Q

Fill in the blanks:

A

CMS1 is characterised by hyper-_____.
This may lead to creation of neo-_____ and increased _____.
Leading to an enhance _____ response.

40
Q

Which therapy may tumours in the CMS1 group be more susceptible to and why?

A

Immune therapy due to its high antigenicity, especially with MSI.

41
Q

Which group has the worst prognosis out of CMS2, 3, or 4?

A

4

42
Q

Which CMS group is associated with marked stomach fibrosis?

A

CMS 4

43
Q

Describe CMS2

A
  • SCNA high
  • Wnt and Myc activation
44
Q

Describe CMS 3

A
  • Mixed MSI
  • SCNA low
  • CIMP low
  • metabolic dysregulation
45
Q

Describe CMS4

A
  • SCNA high
  • Stromal infiltration
  • TGF-b activation
  • angiogenesis
  • worse relapse-free and overall survival
46
Q

Which human cancer type has the
- lowest
- highest
Somatic mutation prevalence?

A
  • lowest: pilocytic astrocytoma
  • highest: melanoma