19.06.04 Lynch syndrome and FAP Flashcards
Proportion of colorectal cancers (CRC) worldwide that are sporadic
85%
Proportion of colorectal cancers (CRC) due to lynch syndrome
3-5%
What genes are mutated in Lynch S
Mismatch repair (MLH1, MSH2, MSH6, PMS2.
Prevalence of Lynch syndrome
1/250 (most common form of predisposition to cancer)
Cancer types according to MMR genes
- MLH1 mutations lead to GI cancers
- MSH2 associated with a greater variety of cancers
- MSH6 and PMS2- associated with reduced age-related penetrance.
Mean age of onset
45 years (often higher in MSH6 and PMS2)
Mutation spectrum in Lynch S
80-90% in MLH1 and MSH2, 7-10% in MSH6, <1% in PMS1/2.
What gene is upstream of MSH2, who’s 3’ end is deleted in 3% of cases
EPCAM
What happens when 3’ end of EPCAM is deleted
Creates a fusion EPCAM-MSH2 fusion. Leads to hypermethylation of MSH2 promoter and loss of MSH2 expression
Other genetic alterations in MMR genes
- 10mb inversion on chromosome arm 2p, disrupting MSH2
- A LINE-1 mediated retrotranspositional insertion in PMS2
- Methylation of MLH1 promoter
What clinical criteria can be used in Lynch Syndrome
- Amsterdam (developed to identify Lynch patients for research studies)
- Bethesda guidelines (more sensitive but less specific than Amsterdam criteria)
Routine pre-screen testing in tumour samples for Lynch syndrome
- Immunohistochemistry
- MSI (microsatellite instability)
- MLH1 hypermethylation
- BRAF V600E
What is immunohistochemistry
Testing presence/absence of proteins in tumour slides using antibodies.
How sensitive is IHC for DNA MMR deficiency
95%
What are the MMR heterodimers
- MSH2/MSH6
- MLH1/PMS2
Would we expect MSI if loss of MMR protein expression on IHC
Yes
When do you get normal IHC but MSI
-Missense mutations that result in a non-functional immunoreactive protein (5% cases)
What is MSI
Microsatellite instability. Genetic instability characterised by length alterations to microsatellites
How is MSI tested
- Panel of 5 monomorphic markers assessed.
- Comparison between tumour and normal tissue
- 10-15% of sporadic CRCs have MSI
3 outcomes of MSI testing
- Tumour has 2 or more altered mononucleotide markers = MSI high.
- Microsatellite stable
- One marker shows instability. Insufficient to be classed as instability associated with Lynch Syndrome.
What proportion of sporadic cancers have hypermethylation of MLH1 promoter
15%
Loss of MLH1 staining could be due to what
- Somatic hypermethylation of MLH1 promoter (rarely germline)
- 3’ EPCAM deletions
- MLH1 mutations
What BRAF mutation is associated with MLH1 hypermethylation
V600E (Val600Glu)
What is BRAF
Oncogene
Does BRAF commonly occur in MSI high tumours
No, usually non-MSI high SPORADIC tumours
Why is BRAF V600E testing used as a pre-screen
Avoids unnecessary MMR gene screening