PhD Doctoral Theses Bart's.Patients with longstanding, extensive colonic inflammation from inflammatory bowel
disease (IBD) have a significantly increased risk of developing colorectal cancer (CRC).
As a result, these patients are entered into endoscopic surveillance programmes with
the aim of detecting and treating precursor dysplastic lesions and early cancers.
However, surveillance is complicated by high cost, patient discomfort and missed
pathology. The majority of patients with dysplastic lesions do not develop cancer, and
many IBD patients with cancer do not have a preceding dysplasia diagnosis. Moreover,
the histological grading of IBD-associated dysplasia suffers from significant interobserver
variability, and the most appropriate clinical management strategy for patients
with evidence of dysplasia remains uncertain. Accurate CRC risk stratification in IBD
represents an unmet clinical need; these clinical challenges reflect our poor
understanding of the molecular processes underpinning IBD-mediated CRC.
We now recognise that clonal evolution underpins IBD-mediated carcinogenesis,
whereby epithelial cells acquire heritable genomic changes that provide them with a
survival advantage in an environment of relapsing-remitting inflammation. In this
thesis, I begin with an assessment of long-term patient outcomes following the
endoscopic resection of neoplastic lesions in patient with IBD. Next, I analysed the
pattern of clonal evolution over time and space in colonic mucosa by measuring the
burden of genomic alterations accumulating during transition from histologically
normal epithelium through to dysplasia and cancer, with a particular focus on the role
of chromosomal copy number alterations. The results generated from these studies are
leveraged to compare the pattern of genomic alterations in epithelial tissue samples
(both dysplastic and non-neoplastic) from patients who subsequently progress to CRC,
against samples from patients who never progress. In particular, I highlight the
translational potential of the generated findings in the development of a novel clinically
applicable “evolutionary biomarker” of cancer risk in patients with IBD
