Lynch Syndrome

Question 1

How do Lynch syndrome pt’s clinically present?

Answer 1

Increased risk of many cancers.
Many are asympotmatic until presentation with symptoms of CRC (incidence higher in men than women)
Younger than typical CRC pt

70% cancers in splenic flexure (better survival rate)

Question 2

What is incidence of Lynch in causing CRC?

Answer 2

3000/100,000 cases

Compared to 10/100,000 being FAP

Question 3

Where did Lynch start?

Answer 3

Descendants of man born in Plattenhardt germany in 1796.

Question 4

What are microsatellite instabilities caused by?

Answer 4

Defects in DNA MMR (inherited as germ line defects) as in lynch syndrome.

Somatically aquired thru epigentic silencing of MLH1.

MSH2 / MLH 1 account for 90% of cases

Question 5

What are 6 MMR proteins? Which ones are implicated in high levels of microsatellite instability?

Answer 5

MSH2/3/6
MLH1/3
PMS1/2

Mutations in MSH2/MLH1 results in high MSI

MSH6 -> lower levels of MSI

Question 6

What is slippage in regards to the MSI pathway? What kinds of slippage are there?

Answer 6

Error that can occur during replication of MS sequences.

Backward slippage => insertion of extra sequence
Forward slippage => deletion

Question 7

Describe in detail the MMR pathway in Eukaryotes

Answer 7

1. Mismatch recognized
2. MSH2/6 binds at mismatch site
3. MLH1/PMS2 recruited by MSH2/6
4. MSH2/6 matchmake with MLH1/PMS2
5. Correct strand recognized
6. MLH1/PMS2 act as endonuclease cleaving on either side of mismatch
7. Exonuclease degrades section containing mismatch
8. Gap in DNA resynthesized by DNA pol III and sealed with DNA ligase

Question 8

How can we detect MSI scientifically?

Answer 8

PCR using MSI markers

Immunohistochemistry

Question 9

How is PCR to detect MSI designed?

Answer 9

Use restriction enzymes to recognize seq. B4 repeat. Then the length of repeat sequences can be run on a gel and larger repeats wont move as far on gel.

Question 10

How many MSI loci are there? Which are mono repeats, which are di?

Answer 10

BAT25/26 - mono repeat

D5S356/D2S123/D17S250 - dinucleotide repeats

Question 11

IF you are doing a staining and there is an absence of one or more of the MMR gene proteins, what could this mean?

Answer 11

Suggests the presence of an MSI. These proteins should form dimers.

Loss of MLH1 is almost always coupled with loss of PMS2

Loss of PMS2 is accompanied with loss of MSH6

Question 12

When should you start colonoscopy screenings in lynch syndrome patients?

Answer 12

Age 20-25 (every 1-2 years)

Question 13

What is the Amsterdam criteria re: Lynch syndrome?

Answer 13

1. Three relatives with HNPCC associated cancer (one being a 1st degree relative)
2. Cases in 2 generations
3. One cancer case dx b4 50yo

Question 14

What is the Bethesda criteria in re: Lynch?

Answer 14

Meet one of these criteria:

1. Amsterdam criteria
2. Pt

Question 15

What are related subtypes of Lynch syndrome?

Answer 15

Consitutional MMR-D
-> increase in childhood cxs, hematological malignancies.

PPAP: Polymerase proofreading associated polyposis (Lynch like phenotype)
->POLE/POLD1 genes = Lynch like syndrome

Turcot syndrome ( Brain cx)
-> MMR mutations or APC
-FAP: medulloblastoma
Lynch: glioblastoma

Muir Torre sndrome (Skin manifestations)

Question 16

Which MMR pathway mutation increased liklihood of prostate cancer in Lynch patients?

Answer 16

MSH2