Dr Alan Donaldson Consultant in Clinical Genetics Bristol Why do tumour analysis To identify 15 of individuals whose colon cancer may be due to Lynch syndrome for DNA analysis 15 of colon cancers are MSI high ID: 335730
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Slide1
Tumour Analysis-Lynch Syndrome
Dr Alan Donaldson
Consultant
in Clinical Genetics
BristolSlide2
Why do tumour analysis?
To identify 1-5% of individuals whose colon cancer may be due to Lynch syndrome, for DNA analysis.
~15% of colon cancers are MSI high.
Generally have a better outcome.
Poorer response to 5 Fluorouracil?Slide3
Lynch Syndrome.
Hereditary non polyposis colorectal cancer – HNPCC.
Autosomal Dominant disorder.
Due to mutations in one of the mismatch repair genes.
MSH2 50%
MLH1 40%
MSH6 ~7%
PMS2 <5%
(TACSD1) ~1-2%
Accounts for 1-5% of all colon cancers.Slide4
Mismatch repair function.
MSH6 MSH2 MSH3
TTT TTTT TTT TTTTT
TTTTTTTT TTTTTTTTTTTTTT
PMS2 MLH1
HmutS
HmutS
HmutL
PMS1
MLH3
?Slide5
Amsterdam Criteria
Three or more family members, one of whom is a first degree relative of the other two, with HNPCC-related cancers*.
Two successive affected generations.
One or more of the HNPCC-related cancers diagnosed before age 50 years.
Exclusion of (FAP).
* Colon, endometrial, small intestine, hepatobiliary, urinary tract.Slide6
Immunohistochemical (IHC) staining of the mismatch repair proteins.
MLH1 PMS2
MSH2 MSH6Slide7
Microsatellite instability (MSI) 1.Slide8
Normal tissue
Tumour tissue
Arrows indicated additional peaks
and microsatellite instability.Slide9
Sporadic loss of MLH1.
10-15% of all colorectal cancers.
Associated with DNA methylation.
Associated with BrafV600E in colonic tumours, but not endometrial.Slide10
Advantages / disadvantages of MSI.
Advantages.
Better sensitivity & Specificity than IHC.
Able to detect BRAFV600E mutations.
Disadvantages.
More expensive than IHC.
Doesn’t tell you what gene is involved. Slide11
Who is ordering these tests?
Genetics
Dermatology
Oncology
Gynaecology
Surgery?
Pathology?Slide12Slide13
Any Questions?