Download Tumour Analysis-Lynch Syndrome

Tumour Analysis-Lynch
Syndrome
Dr Alan Donaldson
Consultant in Clinical Genetics
Bristol
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?
Lynch Syndrome.
Hereditary non polyposis colorectal cancer – HNPCC.
•
•
Autosomal Dominant disorder.
Due to mutations in one of the mismatch repair
genes.
–
–
–
–
–
•
MSH2
MLH1
MSH6
PMS2
(TACSD1)
50%
40%
~7%
<5%
~1-2%
Accounts for 1-5% of all colon cancers.
Mismatch repair function.
MSH6
MSH2
MSH3
HmutS
HmutS
TTT TTTT
TTTTTTTT
TTT
TTTTT
TTTTTTTTTTTTTT
?
PMS1
MLH3
HmutL
PMS2
MLH1
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.
Immunohistochemical (IHC) staining of the
mismatch repair proteins.
MLH1
PMS2
MSH2
MSH6
Microsatellite instability (MSI) 1.
Normal tissue
Tumour tissue
Arrows indicated additional peaks
and microsatellite instability.
Sporadic loss of MLH1.
• 10-15% of all
colorectal cancers.
• Associated with DNA
methylation.
• Associated with
BrafV600E in colonic
tumours, but not
endometrial.
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.
Who is ordering these tests?
Dermatology
Oncology
Gynaecology
Surgery?
Pathology?
Genetics
Any Questions?