Lynch Syndrome

Genes involved in MMR
MSH2 - MSH6
MLH1 - PMS2
All Tumour Suppressor Genes (Caretakers)

Clear family history of dominantly inherited early-onset colon cancer but generally do not have polyps

Why does this defect lead to bowel cancer in particular?

Transforming Growth Factor B (TGFB) is a strong inhibitor of cell proliferation in the colorectum

It acts on a cell-surface receptor of which the TGFB receptor 2 (TGFBR2) protein is part

The TGFBR2 gene contains a run of 10 consecutive A nucleotides

MMR-deficient cells are liable to slippage in this region, rendering the TGFR2 protein non-functional

Epigenetics

Lynch syndrome can also be caused by a deletion of the 3' end of the EPCAM gene, which leads to methylation of the promoter of MSH2 so the gene is silenced in EPCAM-expressing tissues. OR spontaneous methylation of CpG islands in 5'-UTR of MLH1 leads to transcriptional silencing. This can be mosaic throughout cells leading to a milder phenotype, also reversible on transmission to offspring so can show non-mendelian pattern of inheritance.

FAP

Autosomal dominant disorder

Due to mutations in APC
2nd decade of life start developing 1000s of colonic polyps

These can become enlarged and bleed

Can become cancerous

Mutations in APC - lead to a truncated protein - loss of function

Normally protein product regulates the b-catenin pathway (modulates cell growth, apoptosis etc)

	Created by Ellie Quinn almost 11 years ago

Note on Cancer Syndromes, created by Ellie Quinn on 14/02/2014.