HNPCC

Question 1

1-2% of all colorectal cancers are due to what?

Answer 1

HNPCC

Question 2

What is the mode of inheritance for HNPCC?

Answer 2

Autosomal dominant

Question 3

HNPCC is caused by what?

Answer 3

Mutations in the mismatch repair genes (MLH1, MSH2/EPCAM, MSH6, PMS2)

Question 4

What are the cancer risks associated with HNPCC?

Answer 4

• Colon cancer by age 70: 70% risk in males and 35% in females
• Endometrial cancer by age 70: 40% risk in females

Question 5

What is a key characteristic of HNPCC tumours?

Answer 5

MSI positive

Question 6

What is the breakdown of mutations across the mismatch repair genes in HNPCC?

Answer 6

• MLH1/EPCAM/MSH2 = 90% (30% MLH1; 60% MSH2; less than 1% EPCAM)
• MSH6 = 7-10%
• PMS2 = less than 5%

Question 7

What is the basic mechanism of mismatch repair?

Answer 7

• Error in newly synthesised strand
• Binding of mismatch proofreading proteins
• DNA scanning detects nick in new DNA strand
• Strand removal
• Repair DNA synthesis

Question 8

What a microsatellite instability?

Answer 8

• Genetic instability results in subtle sequence alterations within microsatellites
• In HNPCC it is due to a defect in the cells ability to repair nucleotide mismatches during DNA replication (due to mutation in MMR gene)

Question 9

Which is more sensitive, IHC or MSI testing for HNPCC?

Answer 9

• MSI is more sensitive

- IHC will miss 5% of MSI-H cancers

Question 10

What is the difference between MSI-H and MSI-L tumours?

Answer 10

• MSI-H = at least 40% of markers are unstable
• Less than this = MSI-L
• most HNPCC tumours are MSI-H

Question 11

What is the name of the criteria involved in HNPCC?

Answer 11

Bethesda criteria

Question 12

How does IHC work in the context of HNPCC?

Answer 12

• Loss of expression of MMR genes
• Antibodies against MMR genes
• Tumour cells show loss of expression
• Surrounding cells show normal expression
• won’t detect Missense mutations (1/3 of MLH1)

Question 13

What is the sensitivity of IHC in HNPCC testing?

Answer 13

• Only MLH1 and MSH2 = 85%

- plus MSH6 and PMS2 = 93%

Question 14

Approx 10-15% of sporadic, non-HNPCC tumours have MSI. How do you distinguish from sporadic colon cancer?

Answer 14

• BRAF V600E = most common mutation in sporadic colon cancer (often used as prescreening tool in HNPCC - only BRAF V600E neg cases need screening of MMR genes)
• Methylation of MLH1 promoter is the cause of approx 90% of sporadic cases of MSI and is also found in BRAF V600E positive cases

Question 15

What are some treatment options in HNPCC?

Answer 15

Main existing options:

• Prophylactic surgery
• Colectomy
• Total abdominal hysterectomy and bilateral salpingo oophorectomy