Tumour Analysis-Lynch Syndrome

Dr Alan DonaldsonConsultant 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 50%– MLH1 40%– MSH6 ~7%– PMS2 <5%– (TACSD1) ~1-2%

• Accounts for 1-5% of all colon cancers.

Mismatch repair function.MSH6 MSH2 MSH3

TTT TTTT TTT TTTTTTTTTTTTT TTTTTTTTTTTTTT

PMS2 MLH1

HmutSHmutS

HmutLPMS1

MLH3?

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 peaksand 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?

Genetics

Dermatology

Oncology

Gynaecology

Surgery?

Pathology?

Any Questions?