CRC

Question 1

RF for CRC?

Answer 1

• FAP and HNPCC 50 year, thus AGE – biggest RF
• Low fibre diet
• Obesity
• T2DM!
• Excess EtOH
• Personal or FHX
  UC 5-15X risk, Crohn’s is less

Question 2

3 genes in the classical CRC pathway?

Answer 2

APC, K-Ras and p53 pathway most classical pathway involved in pathogenesis

Question 3

Pathogenesis of MMR pathway

Answer 3

• Tumour suppressor genes which correct for errors in DNA replication
• Defects cause accumulation/variation in DNA sequence called microsatellites.
• Variation in these cause frame shift mutations and thus defective protein
• Germline mutation = HNPCC – get mutations in MLH1, MSH2, MSH6 PMS2 or EPCAM.
• Sporadic mutations are due to hypermethylation in MLH1 promoter . This is an epigenetic phenomenonleading to silenced gene expression and thus not a gene mutation
• MSI-H means they are deficient in MMR, and thus have high numbers of microsatellite variations, and thus more at risk of malignancy
• Thus patients who have MHL1, MSH2, MSH 6 etc present are unlikely to have HNPCC
• If Absent or mutated then likely HNPCC

Question 4

What are the features of cancers with MSI high ?

Answer 4

• Accounts for 15% of all CRC

- MSI – H CRC – arise in proximal colon, lymphocytic infiltrate, poorly differentiates,

Question 5

What are the mutations in HNPCC?

Answer 5

MHL1, MSH2, MSH 6, PSM, EPCAM

Question 6

What is the mode of inheritance of FAP ?

Answer 6

AD

Question 7

What is the mode of inheritance of HNPCC ?

Answer 7

AD

Question 8

Which gene is mutated in FAP?

Answer 8

APC

Question 9

What other cancers are associated with HNPCC?

Answer 9

Endometrial (40%), ovarian, stomach, bowel

Question 10

What is Gardener’s sydnrome?

Answer 10

Also due to APC mutation.

Increase CRC + desmoid tumours, osteomas, epidermal cysts, duodenal tumours and gastric fundic gland polyps.

Question 11

What is the screening for low risk patients i.e. Category 1 ?

Answer 11

FOBT yearly from 50

Question 12

Who is the moderate increase risk (Category 2) for CRC ?

Answer 12

1 st degree relative with CRC before 55
or
2 x 1st or 2nd degree at any age

Question 13

What is the screening for moderate risk (category 2) with CRC?

Answer 13

Colonoscopy every 5 years from 5 or 10 years younger than first diagnosed relative

Question 14

Who are high risk patients (category 3) with CRC

Answer 14

3 x relatives with CRC 
or
2 or family member plus high risk features
- multiple lesions in 1 person
- CRC

Question 15

How are people with FAP screened?

Answer 15

Sigmoidoscopy from 12-15
total colectomy and ileoretal anastamosis one multiple polyp greater than 1 cm
Duodenal screening from 25 or time of colectomy

Question 16

How are people with HNPCC screened ?

Answer 16

Colonoscopy 1-2 yearly from age 25 or 5 years younger than familial case

Question 17

Prevention of HNPCC?

Answer 17

Aspirin

Question 18

What is stage 2 CRC?

Answer 18

Invades full thickness of the bowel and may invade into the pericolonic or perirectal fat

Question 19

What is stage 1 CRC?

Answer 19

Tumour does not invade the full thickness of the bowel wall

Question 20

What is stage 3 CRC?

Answer 20

LN

Question 21

What is stage 4 CRC?

Answer 21

Mets

Question 22

How do you manage stage 1 and 2 CRC?

Answer 22

Resect

Question 23

How do you manage stage 3 CRC?

Answer 23

Resect + adjuvant chemo

• either Capcitabine/5-Fu + Oxaliplatin
• if crusty just use Capcitabine

Question 24

Why do you check K-rase before giving eGFR immunotherapy ?

Answer 24

K-ras is a downstream mutation from the eGFR signalling cascade, thus if you are K-ras mutant, blocking eGFR will not work

Question 25

How do you manage stage 4 CRC?

Answer 25

1. Resect Isolate liver or lung met
2. Check K-RAS
3. Adjuvant chemo - oxaliplatin/capecitabine
4. If K-RAS wild type give Cituximab
   if K-RAS positive give bevacizumab