1. Tumour Analysis-Lynch Syndrome Dr Alan Donaldson Consultant in Clinical Genetics Bristol

2. 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?

3. Lynch Syndrome. Hereditary non polyposis colorectal cancer – HNPCC. Autosomal Dominant disorder. Due to mutations in one of the mismatch repair genes. – MSH250% – MLH140% – MSH6~7% – PMS2<5% – (TACSD1)~1-2% Accounts for 1-5% of all colon cancers.

4. Mismatch repair function. MSH6MSH2MSH3 TTT TTTT TTT TTTTT TTTTTTTT TTTTTTTTTTTTTT PMS2MLH1 HmutS  HmutS  HmutL  PMS1 MLH3 ?

5. 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.

6. Immunohistochemical (IHC) staining of the mismatch repair proteins. MLH1PMS2 MSH2MSH6

7. Microsatellite instability (MSI) 1.

8. Normal tissue Tumour tissue Arrows indicated additional peaks and microsatellite instability.

9. Sporadic loss of MLH1. 10-15% of all colorectal cancers. Associated with DNA methylation. Associated with BrafV600E in colonic tumours, but not endometrial.

10. 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.

11. Who is ordering these tests? Genetics Dermatology Oncology Gynaecology Surgery? Pathology?

13. Any Questions?