Upper gastrointestinal disease in familial adenomatous polyposis
File(s)
Author(s)
Martin, Isabel
Type
Thesis
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder with a lifetime risk of colorectal cancer of nearly 100%. Following colectomy, duodenal cancer is a major cause of mortality. Identifying those at risk is challenging, with no clear biomarker or clear genotype-phenotype relationship. The objectives of this work were to evaluate whether endoscopic surveillance or polypectomy, reduced progression to gastric/duodenal cancer and to identify potential biomarkers of duodenal cancer.
Methodology:
Clinical data were collected from the St Mark’s national polyposis database registry. Patients with and without FAP were included. Duodenal mucosal biopsies, blood, urine and bile were collected and analysed using 16S rRNA, whole-genome sequencing and ultra-performance liquid chromatography-tandem mass spectrometry.
Results:
Endoscopic removal of gastric adenomas failed to completely eradicate gastric cancer risk and five per cent of gastric adenomas, demonstrated high-grade dysplasia.
Endoscopic resection of advanced duodenal adenomas (Spigelman score (SS) III/IV) resulted in a 13% reduction in progression from SSIV to duodenal carcinoma. Whole genome sequencing of duodenal adenomas demonstrated an increase in mutational burden, C>T mutations, gains in chromosome 8 and Cosmic mutational signature one.
Duodenal microbial profiles, identified four dominant phyla, although there was no significant difference according to SS or polyp count.
Metabolomic profiling, identified disordered lipid metabolism and 373 statistically significantly different metabolites in patients with and without FAP.
Conclusion
Five percent of gastric adenomas harbour HGD. Endoscopic surveillance and polypectomy reduce progression to advanced duodenal disease and endoscopic mucosal resection result in lower recurrence rates. Patients with FAP have distinct bile acid and lipid profiles and duodenal adenomas have increased mutational burden and gains on chromosome 8. These potential molecular biomarkers warrant further investigation for early detection and risk stratification of upper gastrointestinal cancers in FAP.
Methodology:
Clinical data were collected from the St Mark’s national polyposis database registry. Patients with and without FAP were included. Duodenal mucosal biopsies, blood, urine and bile were collected and analysed using 16S rRNA, whole-genome sequencing and ultra-performance liquid chromatography-tandem mass spectrometry.
Results:
Endoscopic removal of gastric adenomas failed to completely eradicate gastric cancer risk and five per cent of gastric adenomas, demonstrated high-grade dysplasia.
Endoscopic resection of advanced duodenal adenomas (Spigelman score (SS) III/IV) resulted in a 13% reduction in progression from SSIV to duodenal carcinoma. Whole genome sequencing of duodenal adenomas demonstrated an increase in mutational burden, C>T mutations, gains in chromosome 8 and Cosmic mutational signature one.
Duodenal microbial profiles, identified four dominant phyla, although there was no significant difference according to SS or polyp count.
Metabolomic profiling, identified disordered lipid metabolism and 373 statistically significantly different metabolites in patients with and without FAP.
Conclusion
Five percent of gastric adenomas harbour HGD. Endoscopic surveillance and polypectomy reduce progression to advanced duodenal disease and endoscopic mucosal resection result in lower recurrence rates. Patients with FAP have distinct bile acid and lipid profiles and duodenal adenomas have increased mutational burden and gains on chromosome 8. These potential molecular biomarkers warrant further investigation for early detection and risk stratification of upper gastrointestinal cancers in FAP.
Version
Open Access
Date Issued
2024-04-02
Date Awarded
2026-04-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Clark, Susan
Latchford, Andrew
Sponsor
Royal College of Surgeons of England
St Mark’s the National Bowel Hospital
Imperial College London
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)