5a: Genetic Pathways In Cancer Flashcards
Fill in the blanks:
As neoplasia progresses through _____ lesions, the number of mutation acquired by the lesion _____.
1) Precursor
2) increases
Fill in the blanks:
Selective advantage ensures that _____ acquisition is broadly _____
1) Mutation
2) Consistent
What is oncogene co-operation
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
Which mutation does KRAS often co-occur with?
PIK3CA
What is example of two mutations that co-occur in pancreatic cancers but not often in lung?
KRAS and TP53
Why may pair of mutations co-occur in one tumour but not another?
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.
Give an example of a mutation that is selected against in endometrial cancers with MSI?
TGFRBR2, due to its repeat sequences
Fill in the blanks:
Mutations may select against other mutations.
It is unlikely two mutations will activate the same _____. This will lead to _____ _____.
1) Pathway
2 & 3) mutual exclusion
Which 3 mutations are mutually exclusive in the MAPK signalling pathway?
EGFR, KRAS, BRAF
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 ______.
1) addiction
2) amnesia
What are the 3 genetic pathways of colorectal cancer?
- Chromosomal instability (CIN)
- Microsatellite instability (MSI)
- Chromosome and microsatellite stable
Why is CpG Island Methylator Phenotype colorectal cancer not considered its own genetic pathway despite being well described?
Due to its close link to the MSI pathway
Most sporadic CRCs arise as a result of which mutation?
APC
Which signalling pathway does APC activate?
Wnt signalling
Fill in the blanks:
Approximately __% of sporadic CRC tumours will arise _____ to the _____ _____ (left sided)
1) 70
2) distal
3 & 4) splenic flexure
What % of sporadic tumours will show MSI
10-15%
When does MSI occur?
When there is a failure of the mismatch repair function
What des MSI result in?
Hypermutation/ increased mutation rate
What is ‘redundancy’ in regards to the genome?
If there is a dysfunctional protein, other similar proteins may act to take over the same role.
What are the protein pairs that make up the complex in the DNA mismatch repair pathway?
- MSH2 & MSH6
- MLH1 & PMS2
What causes almost all cases of MSI in sporadic CRC tumours?
MLH1 promoter methylation
Fill in the blanks:
MSH2/_____ dimers and _____/PMS2 _____ function to excise_____ _____.
1) MSH6
2) MLH1
3) dimers
4 & 5) mismatched bases
How many of the proteins in the complexes in mismatch repair must be lost in order for the repair to fail?
Just 1
Will repeats be added/deleted if a loop occurs on the:
- template strand
- newly synthesised strand
- Repeats deleted
- Repeats added
What technology is used to detect microsatellite instability?
PCR
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 ____.
1) adenomatous
2 & 3) phenotypes, genotypes
4) different
5) chemotherapy/treatment
What is CIN in CRC characterised by?
Aneuploidy and allelic loss
Which mutations may be responsible for CIN
CDC4 and TP53
Which genetic pathway in CRC is left/right sided?
MSI - right sided
CIN- left sided
What are some characteristics of MSI colorectal tumours?
- right sided
- mucinous
- have a dense lymphocytic infiltrate
Genetically, what is MSI colorectal cancer characterised by?
- Mutations in: TGFBR2, BRAF, BAX
- Diploid nuclei
- Lack of TP53 mutations
- Little allelic loss
Which mutations in MSI tumours are mutually exclusive with APC mutations and why?
RNF43 and ZNRF3 as they also activate the Wnt signalling pathway
Fill in the gaps:
Tumours with MSI have a _____ prognosis (except after _____), they respond better to _____.
1) better
2) metastasis
3) immunotherapy
What is the consensus molecular subtypes classification related to?
Prognosis
What do tumours in the CMS1 subtype contain?
- MSI
- POLE/POLD1 mutations
- CpG island methylator phenotype
- immune infiltration/activation
- hypermutation
Using 1 word, how could you describe the 4 CMS groups in colorectal cancer?
- CMS1: MSI immune
- CMS2: Canonical
- CMS3: Metabolic
- CMS4: Mesenchymal
What does SCNA stand for
Somatic copy number alteration
Which CMS group is most distinct from CMS1
CMS4
Fill in the blanks:
CMS1 is characterised by hyper-_____.
This may lead to creation of neo-_____ and increased _____.
Leading to an enhance _____ response.
Which therapy may tumours in the CMS1 group be more susceptible to and why?
Immune therapy due to its high antigenicity, especially with MSI.
Which group has the worst prognosis out of CMS2, 3, or 4?
4
Which CMS group is associated with marked stomach fibrosis?
CMS 4
Describe CMS2
- SCNA high
- Wnt and Myc activation
Describe CMS 3
- Mixed MSI
- SCNA low
- CIMP low
- metabolic dysregulation
Describe CMS4
- SCNA high
- Stromal infiltration
- TGF-b activation
- angiogenesis
- worse relapse-free and overall survival
Which human cancer type has the
- lowest
- highest
Somatic mutation prevalence?
- lowest: pilocytic astrocytoma
- highest: melanoma
