Lectures 12, 13 + 14 - Colon Cancer, Lymphomas and Heterogeneity Flashcards
List 3 major mutations found in colon cancer and their percentages
60% show APC mutations
50% show p53 mutations
40% show kras mutations
Describe the features of colon cancer subtype 1
- Chromosomal instability
- Initiating events - APC loss +/ kras/p53 mutations
- Usually in desc colon
- Original lesions = adenomatous polyps
Describe the features of colon cancer subtype 2
- Microsatellite instability
- CpG island methylator phenotype (CIMP+)
- RAS wild-type
- Initiating event = BRAFV600E mutation
- Usually asc colon
- Original lesions = serrated adenomas
Describe the features of colon cancer subtype 3
Less well-defined than types 1 and 2
- Microsatellite stable
- CIMP -ve
- Initiating event = BRAFV600E or Kras mutation
- May occur anywhere in colon
- Original lesion = serrated adenomas
Describe what is meant by chromosomal instability
Continual loss or gain of whole and/or parts of chromosomes, which contributes to tumour heterogeneity, giving rise to a genetically diverse pool of tumour cells
Why do we screen for Kras mutations in colorectal cancer?
Determines suitability for treatment with Cetuximab - won’t work if downstream signalling of EGFR is constitutively active
What change occurs in the BRAFV600E mutation? What does this cause?
Valine to glutamate within kinase domain of BRAF
Constitutively active - drives MAP kinase pathway
What does it mean if a tumour is CIMP +ve?
Stands for CpG Island Methylator Phenotype Positive
Basically means there has been methylation of DNA which means it becomes inaccessible to transcription factors - therefore inhibits transcription.
If it occurs in TSGs, means they are not transcribed - loss of p53 etc…
What are microsatellites?
What is microsatellite instability?
Microsatellites are repeating sequences of 2 - 5 bps which are prone to replication errors.
Usually repaired by MMRs
If MMRs deficient, leads to microsatellite instability as not repaired properly
Which subtype has the best prognosis?
Which is the worst?
1 best
3 worst
Where do lymphomas usually arise?
The germinal centres - sites within secondary LNs where mature B lymphocytes proliferate and differentiate
What are the 2 types of Burkitt lymphoma?
- Sporadic - rarely associated with EBV/malaria
- Endemic - associated with EBV/malaria (malaria makes you more susceptible to EBV)
Describe the genetic changes that give rise to Burkitt lymphoma
Myc region of chromosome 8 translocates onto chromosome 14. Ends up next to IGH region - IGH stimulates increased transcription of MYC gene –> over-expressed –> rapid cell cycle progression –> malignancy
What genetic changes underlie follicular lymphoma?
Translocation of BCl2 gene from chromosome 18 to chromosome 14.
Anti-apoptotic gene, therefore when overexpressed in this translocation, allows cell to resist apoptosis
What genetic changes underlie DLBCL?
Chromosomal translocation of BCl 6 - leads to under-expression - in turn leads to loss of BLIMP1, a TSG
