GI cancer SD Flashcards
inherited mutation at APC gene that increases risk of CRC
familial adenomatous polyposis (FAP)
What is FAP?
- familial adenomatous polyposis
- inherited mutation in the APC gene
- formation of many polyps on the colon mucosa
risk of CRC with FAP
100% lifetime risk
How is FAP diagnosed?
colonscopy and genetic testing
What type of mutations are in the APC gene that cause FAP?
mostly point mutations
What type of gene is APC?
tumour suppressor gene
variant forms of FAP
attenuated FAP - specific APC mutants, fewer polyps
MUTYH-associated FAP - mutations in MUTYH gene implicated in base excision repair, autsosomal recessive inherited
RF for CRC
- diet - red meat, processed meats, dec risk with fibre, chicken, fish
- lack of physical activity
- obesity
- alcohol
- smoking
- genetic predisposition
- protective effetive of aspirin
-> 54% cases preventable through lifestyle
gene mutations that can cause CRC
KRAS
BRAF
Where is IBD related CRC most common?
ascending colon
Where is sporadic CRC most common?
descending colon, sigmoid colon and rectum
How long does it take for adenoma to develop into advanced carcinoma?
17 years
How long does it take for progression from early carcinoma to metastasis?
1.8 years
staging system for CRC
Duke’s Stage A-D
most common site for metastases in CRC
liver (50% of CRC patients)
2nd most common site for metastases in CRC
lung
Vogelstein model
- model of how CRC arises
- stepwise accumulation of mutations/epigentic changes and how these form tumours in CRC
- genes - APC, KRAS, p53
screening for CRC
- faecal occult blood test
- measure of blood in stool
- testing cards sent to home, posted to lab for analysis
guaic faecal occult blood stool test
card coated with guaic resin, faeces applied by patient
hydrogen peroxide developer solution applied
detects haemoglobin activity
limitations to the guaic faecal test
- red meat, cauliflower, uncooked veg, haemorrhoids all give false positives
- high vitamin C gives false negative
gold standard screening for CRC
colonoscopy
strict diet days before colonoscopy
low fibre
only clear liquids
laxatives to prep bowel
difference between flexible sigmoidoscopy and colonscopy
- sigmoidoscopy only covers the descending colon
- colonscopy provides full coverage of colon
advantages of sigmoidoscopy over colonoscopy
- like colonoscopy, can remove polyps/ademonas and take biopsies
- only covers descending colon but this is where most sporadic CRC tumours originate, coverage for 70-80% CRC cases
- no sedation required
- reduces cost
- shorter duration (10mins vs 30mins)
When would colonoscopy be used instead of sigmoidoscopy?
preferred for colitis-associated CRC
main Tx for CRC
surgery to remove the tumour and chemotherapy to reduce the risk of metastases
chemotherapy can be given before surgery to shrink tumour size or after surgery to reduce the chance of recurrence
When does adjuvant chemotherapy usually begin after surgery?
6 weeks after
Is radiotherapy used?
no, not common
USED IF:
- not clear if tumour completely removed (attached to lining of abdomen)
- patient not healthy enough for surgery
- more common in rectal cancer as adjuvant therapy to prevent recurrence (stage 2-3)
3 signalling and targeted therapies for CRC
- EGFR inhibitors
- VEGFR inhibitors
- immunotherapy
How to EGFR inhibitors work?
target EGFR (epidermal growth factor R) that promotes tumour growth
How to VEGFR inhibitors work?
target VEGF (vascular endothelial growth factor) that promotes growth of neovasculature
How does immunotherapy work?
- target PD-L1 which is expressed on tumours to block immune response
- PD-1 inhibition increases immune response to the tumour
- given to patients not responding to chemotherapy
How can EGFR signalling promote CRC?
- EGFR activation stimulates multiple downstream pathways
- these drive cellular proliferation and promote cell survival (anti-apoptosis)
- components frequently mutated in CRC - activates the pathways irrespective of EGFR activity
- KRAS
- BRAF
- PI3K
- PTEN
How can EGFR signalling promote CRC?
- EGFR activation stimulates multiple downstream pathways
- these drive cellular proliferation and promote cell survival (anti-apoptosis)
- components frequently mutated in CRC - activates the pathways irrespective of EGFR activity
- KRAS
- BRAF
- PI3K
- PTEN
What should be tested before Tx for metastatic CRC suitable for systemic Tx? Why?
RAS and BRAF V600E mutations in all patients suitable for systemic anti-cancer Tx
it effects Tx choice, mutated receptors, resistance
WT patients can receive cetuximab/Panitumumab -> EGFR MAbs
mutate RAS means this therapy is ineffective
What does VEGF do?
tumour secretes VEGF
VEGF increases blood vessel expression and movement to tumour
tumour has increased blood supply
MAb for VEGF
Bevacizumab (Avastin)
Where do mutations in KRAS mostly cause CRC?
sigmoid
rectum
Where do mutations in BRAF mostly cause CRC?
ascending
tranverse colon
genetic alterations that can be in metastatic CRC that prevent cells from repairing damaged DNA
dMMR - mismatch repair deficiency
MSI-H - high microsatelite instability
What do dMMR and MSI-H cause?
- prevent cells from repairing DNA damage
- leads to high rates of DNA mutations
- some mutations can lead to production of abnormal antigens that can be targeted by immune cells
MAb that targets PD-L1 (programmed death ligand 1)
Pembrolizumab
