Characterising novel variants in candidate genes predisposing to colecteral adenoma and carcinoma.

Project supervisors-Dr J Cheadle and Prof J Sampson.
Institute of Medical Genetics,Cardiff University, Heath Park, Cardiff, CF14 4XN.

Inherited factors are thought to play a major role in at least 15% of ccolorectal cancers (CRCs),  but established CRC predisposition genes account for only a minority of these.

Our laboratory was recently responsible for a major advance in the understanding of of inherited predisposition to bowel cancer.  We showed that biallelic germline defects in the base excision repair gene MYH predispose to the development of multiple colecteral adenoma and carcinoma.  (Al-Tassan et al. Nature Genetics 2002, Sampson et al. Lancet 2003).   We are now screening for further genes that may predispoe to CRC by utilising the resources of the Wales Polyposis Register, the Welsh Polyp study and cases with multiple colorectal adenomas with or without CRC from collaborating laboratories.

By using a combination of dhPLC and direct sequencing, we have assayed 6 candidate genes and identified 64 novel variants, including 23 coding region changing substitutions.  We are currently investigating the pathogenecity of these variants.  This work may provide new information for genetic testing and surveillance of gene carriers which can greatly improve their life expectancies through the detection and treatment of pre-malignant growths or very early cancers.