HNPCC Flashcards
(4 cards)
Mechanism of HNPCC
o Autosomal dominant disorder
o Predisposes to colorectal cancer, endometrial cancer and some other malignancies
o Caused by germline mutations affecting mismatch repair genes (MMR)
o MSH2, MSH6, MLH1, PMS2
o MMR pathogenic variant – prevents mismatch repair from occurring
o Microsatellites are repetititve regions of DNA- therefore errors in replication occur more frequently
o Therefore, mismatch repair deficiency will often lead to acquiring further damaging variants resulting in tumour formation and also microsatellite instability
What tumour studies can be done and why are these beneficial?
- Microsatellite instability
- Supports evidence that tumour has arisen due to lynch
- Mutations in MMR genes affect genomic stability: leading to contraction or expansion of repetitive regions of DNA (microsats): leads to MSI instability.
- IHC: tumour staining to look for loss of protein expression
- Evidence of high MSI and loss of protein expression on IHC provides evidence that tumour arisen due to HNPCC
- Tests to determine whether tumour arisen sporadically:
- MLH1 promoter methylation
- This would indicate loss of MLH1 is due to promoter meth and not a intragenic mutation.
- Test for presence of V600E variant in BRAF is a marker of sporadic colorectal cancer
What is IHC and why is it useful?
o Used to identify presence or absence of proteins within a sample
o Tumour sample from patient can be tested
o IHC: Uses antibodies raised against a specific antigen
o Antibodies often tagged with fluorescent label
o Staining indicates presence of that protein (antigen on that protein)
- Loss / absent staining indicates absence of protein or dimer partner
- Therefore this can give an indication of presence of pathogenic mutation
- Loss of PMS2/MLH1, but no MLH1 genetic mutation may indicate MLH1 promoter hypermethylation which would cause inactivation of MLH1
HNPCC limitations of testing
o PMS2 pseudogenes- makes it difficult to determine whether MLPA/sequencing has detected presence of PMS2 or pseudogenes
o We have a rider in report.
