familial adenomatous polyposis inherited mutation in the APC gene formation of many polyps on the colon mucosa

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

model of how CRC arises stepwise accumulation of mutations/epigentic changes and how these form tumours in CRC genes - APC, KRAS, p53

GI cancer SD Flashcards by Sarah Ramsbottom

inherited mutation at APC gene that increases risk of CRC

familial adenomatous polyposis (FAP)

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What is FAP?

familial adenomatous polyposis
inherited mutation in the APC gene
formation of many polyps on the colon mucosa

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risk of CRC with FAP

100% lifetime risk

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How is FAP diagnosed?

colonscopy and genetic testing

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What type of mutations are in the APC gene that cause FAP?

mostly point mutations

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What type of gene is APC?

tumour suppressor gene

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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

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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

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gene mutations that can cause CRC

KRAS

BRAF

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Where is IBD related CRC most common?

ascending colon

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Where is sporadic CRC most common?

descending colon, sigmoid colon and rectum

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How long does it take for adenoma to develop into advanced carcinoma?

17 years

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How long does it take for progression from early carcinoma to metastasis?

1.8 years

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staging system for CRC

Duke’s Stage A-D

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most common site for metastases in CRC

liver (50% of CRC patients)

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2nd most common site for metastases in CRC

lung

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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

1. EGFR inhibitors 2. VEGFR inhibitors 3. 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?

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