Molecular genetic and endoscopic studies of duodenal polyposis

Duodenal polyposis and cancer have become a key issue for patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). The incidence of duodenal adenomas in MAP appears to be lower than in FAP but the very limited available data suggest a comparable increase in relative risk and lifetime risk of duodenal cancer. The work reported in this thesis addressed gaps in current knowledge in endoscopic and molecular genetic aspects of duodenal polyposis in MAP and FAP. A prospective study examined the impact of chromoendoscopy on assessment of the duodenum in MAP and FAP. It demonstrated enhanced adenoma detection in both MAP (p=0.01368) and FAP (p=0.002516), but did not affect measurement of adenoma size. In both conditions there was a significant increase in Spigelman stage after chromoendoscopy compared to endoscopy without dye-spray. A European collaborative project established a cohort of 207 MAP patients who had undergone surveillance upper GI endoscopy. There was a cumulative incidence of 30% of duodenal adenomas, and a 2.3% cumulative incidence of duodenal adenocarcinoma in MAP by 70 years of age. Patients that were Y179C homozygotes had a greater number of duodenal adenomas (and consequently higher Spigelman score) than patients with either two truncating mutations, G396C homozygotes, or G396D / Y179C compound heterozygotes, consistent with a more severe colorectal phenotype previously reported in Y179C homozygotes. To investigate the somatic mutation rate and patterns of mutations in MAP and FAP duodenal adenomas, exome sequencing, Sanger sequencing and arrayCGH of adenoma tissue and matched blood DNA from patients undergoing upper GI surveillance was performed. This demonstrated a higher load of somatic mutation in MAP than FAP adenomas (p=0.035). With the exception of APC and KRAS mutations, there were very few somatic mutations in genes that have been found to drive colorectal tumourigenesis, but several other genes including PLCL1 were found to be recurrently mutated in duodenal adenomas, suggesting that distinct molecular genetic pathways to adenoma development may be operating in the duodenum