Molecular Basis of Colon Cancer Flashcards

1
Q

What percdentage of colorectal cancer patients have a FH?

A

~ 25%

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2
Q

What percentage of cases have a causitive mutation identified?

A

5-6%

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3
Q

What are the 2 familial syndromes that result in increased familial dysposition to colon cancer?

A
  • Familial Adenomatous Polypoisis (FAP)

- Hereditary Nonpolypoisis colon cancer (HNPCC or Lynch syndrome)

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4
Q

How is Familial Adenomatous Polypoisis inherited?

A

Autosomal dominant

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5
Q

What are the features of FAmilial adenomatous polypoisis?

A

LArge number of polyps (100s or more) developing from adolescence onwards
- 90 % patients also have pigmented lesions in retina (CHRPE)

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6
Q

What is the gene defect associated with FAP?

A
  • Adenomatous polyposis coli (APC)
  • Usually creates shorter protein
  • Chromosome 5 q21-22
  • 2843 amino acids
  • Mostly nonsense or frameshift mutations
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7
Q

How do you test for gene defect?

A

Direct sequencing

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8
Q

What greatly increases an individuals likelyhood to have colorectal cancer

A

If they have both copies of a APC mutation

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9
Q

What does APC do?

A
  • Binds Beta-catenin

- Binds microtubules through EB1

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10
Q

What is Beta-catenin?

A
  • APC binds to B-catenin in cytoplasm and mediate degradation keeping levels low
  • Binds to transcription factors and stimulates transcription factors
  • Involved in Wnt signalling
  • Found in adherence junctions through other proteins attaches actin to adherence junction
  • If Beta catenin is mutated complex is unstable making adherence junction not so tight, can lose polarity and aberrant cell migration -> cancer
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11
Q

What is Wnt signalling?

A

Wnt signal binds to receptor and inactivates APC which leads to stable B-catenin (not degraded) and an active TCF complex.
Transcription of Wnt-Responsive genes leadis to proliferation of gut stem cells

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12
Q

What does EB1 do?

A
  • Binds and makes conncetions betweeen microtubules and chromosomes
  • If EB1 and APC not bound properly chromosome is not attached properly to spindle at mitosis abborhent division -> chromosome instability -> cancer
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13
Q

How long does it take for a stem cell to reach the top of the crypt?

A

~ 5 days

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14
Q

Where is the Wnt pathway active?

A

Bottom section of crypt, inactive further up pathway

- When mutation proliferation can happen higher in crypt

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15
Q

What extra-intestinal problems can FAP cause?

A
  • Masses of benign tumours
  • Jaw cysts
  • Sebaceous cysts
  • Osteomata
  • Pigmented lesions of the retina (CHRPE)
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16
Q

When are mutations in APC seen?

A
  • FAP
  • Sporadic tumours
  • Mutations alone not suffiecient to cause cancer
17
Q

How is Hereditary Nonpolyposis colorectal cancer (Lynch syndrome) inherited?

A

Autosomal dominant

18
Q

What percentage of colon cancers are a result of Lynch syndrome?

A

~3%

19
Q

What other cancers can be a result of Lynch syndrome?

A
  • Endometrium
  • Ovarian
  • Small intestine
  • Stomach
20
Q

What are the 4 different genes potentially responsible for Lynch syndrome?

A
  • MLH1 - 50%
  • MSH2 - 40%
  • MSH6 - 7-10%
  • PMS1 - <5%
    Usually a result of DNA mismatch
21
Q

What do the genes which when mutated cause lynch syndrome do?

A

Mismatch repair genes, ring structure

22
Q

What gene regions are more susceptible to errors?

A
  • Repetitive regions (microsatelites)

- Called microsatelite instability

23
Q

How are gene defects detected?

A
  • Immohistochemical protein staining
  • Allows you to apply an antibody to a specific histologcal section;
  • If protein is present within the sample -> dark stain, +ve for protein,
  • No dark stain = negative for protein
24
Q

How can you compare FAP to HNPCC?

A
  • Large number of polyps in FAp, low number in HNPCC
  • Low mutation rate in FAP, high in HNPCC
  • Penetrance ~100% for FAP, approx 80% for HNPCC
25
Q

What is the average age of onset of FAP and HNPCC?

A

~ 40

26
Q

What can people do if they find they have FAP or HNPCC or a FH of the disease

A
  • Offered regular screening from a young age

- Patients often elect to have their colon removed

27
Q

How is screening done in Scotland for FAP and HNPCC?

A
  • > 50 years screened every 2 years for occult blood, and if positive then colonoscopy
  • If known FAP/HNPCC - biannual colonoscopy from 25 years
  • High to moderate risk - colonoscopy every 5 years from age 50 - 75
28
Q

What is meant by high to moderate risk of colon cancer?

A
  • People with 3 or more affected relatives in a first degree kinship with each other (none less than 50 years old)
  • Two affected relatives less than 60 years old in a first degree kinship with each other, or two affected relatives with a mean age less than 60 years old in a first degree kinship
29
Q

What are patients with colon cancer screened for in Scotland?

A

Microsatelite instabilty testing to increase diagnosis of lynch syndrome

30
Q

What protein is overexpressed in the majority of colorectal cancers?

A

EGFR

31
Q

What are the other major risk factors for colon cancer other than genetics?

A
  • Diet
  • Overweight 25% increased
  • Obese 50% increased risk
  • Alcohol (40% increased risk if >5 units a day)
32
Q

What study looks at cancer and nutrition links?

A

EPIC study

  • European Prospective Investigation into Cancer and Nutrition
  • > 500k ppl
  • Recruited 93 - 99
  • Follow for at least 10 years
33
Q

What foods increase/reduce colon cancer risk?

A
  • High fibre reduces risk
  • Fish reduces
  • Red and processed meat increases risk
34
Q

Why are the results the way they are in relation to food?

A
  • Less time in bowel
  • Bile salts pass through more quickly
  • Presence of anti-oxidants and folate in fruit and vegetables
  • Cooking methods
35
Q

What common drug is thought to prevent the risk of colon cancer?

A

Aspirin (low dose can decrease pre-cancerous lesions)

36
Q

How can aspirin protect against colorectal cancer?

A
  • Inhibit COX-2 (as it is an NSAID)
  • COX-2 increased in early stages of colorectal cancer
  • Increased prostaglandin synthesis
  • Stimulates proliferation and angiogenesis
  • Inhibits apoptosis
  • could cause increased risk of CV problems (prostaglandins regulate BP)
37
Q

What does EGFR do?

A
  • Dimerises in response to EGF
  • Tyrosin Kinase -> once dimerised sends signal down to nucleus to stimulate proliferation, metastasise, inhibit cell death
38
Q

What does cetuximab do?

A

blocks EGFR - only used where wildtype Kras