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Factors influencing decisions genetic syndromes ESO-ESSO Masterclass Cascais, Portugal 2011 Professor Sir John Burn MD FRCP FRCPCH FRCOG FMedSci Institute of Human Genetics, Newcastle University, UK With thanks to Professor Marco Novelli UCL London for several teaching slides used in this presentation Institute of Human Genetics Newcastle University Centre for Life, Newcastle UK
Multiple adenocarcinomas in colon (synchronous/metachronous tumours).
Tumours at other sites:
Endometrial, stomach, uroepithelial, small bowel, bladder, pancreatobiliary, brain, skin .
Early age of tumour development (40+).
The two hit hypothesis Predisposed tumour All cells second hit
Lynch syndrome Endometrial Carcinoma Bertha Ted 3 CRC 9 skin cancers Family from which DNA used to Demonstrate hMSH2 mutation by Kolodner’s group 1993: 1 st of the MISMATCH REPAIR GENE DEFECTS 14 years ago
MMR genes are caretaker genes. Think of computer spell checker
MSS MSS MSS MSI-H MSI-H BAT26 NR21 BAT25 NR24 MONO27 Normal pattern MSI testing with quasimonomorphic 5 marker panel: no need to test normal tissue Normal pattern
Deletion in upstream EPCAM gene removes MSH2 promoter leaving gene methylated Deletions Removing the Last Exon of TACSTD1 Constitute a Distinct Class of Mutations Predisposing to Lynch Syndrome Marietta E. Kovacs,1 Janos Papp,1 Zoltan Szentirmay,2 Szabolcs Otto,3 and Edith Olah Human Mutation 2009;30:197 TACSTD1 MSH2 5KB
Loss of MLH1/PMS2 expression MSH2 MSH6 PMS2 MLH1
Implications of loss of expression of Mismatch Repair proteins.
Not diagnostic of Lynch syndrome.
Up to 10% of sporadic tumours lose MLH1 / PMS2 expression (due to MLH1 promoter methylation).
Strong +ve correlation of loss of staining MSH2/6 with germline mutation.
Suggests further genetic analysis may be required.