Integrating Epidemiological and Genomic Factors to Inform Outcomes in Barrett’s Oesophagus and Oesophageal Adenocarcinoma
The incidence of oesophageal adenocarcinoma (OAC) has rapidly increased, and its prognosis remains poor. Barrett’s oesophagus (BO) is considered the precursor to OAC, however, BO is not apparent adjacent to tumour in nearly half of OAC patients. We have previously demonstrated that patients with BO-adjacent tumours (BO+ve OAC phenotype) have a favourable prognosis compared to those without evidence of BO adjacent to the tumour (BO-ve OAC phenotype). It has been suggested that the BO-ve OAC tumour phenotype may arise independently of BO. Recent experimental and computational studies show that all OACs likely arise from BO, even if this precursor lesion is not histologically apparent adjacent to the tumour. However, there is a lack of consolidated clinical, epidemiological and molecular data to examine this question.
In this thesis, I used orthogonal approaches to examine the overlap between the BO+ve OAC and BO-ve OAC phenotypes and explain the aetiology and the observed altered prognosis. To achieve this, I assembled a large cohort (n=4,695) comprising BO+ve OAC cases (n=1,235), BO-ve OAC cases (n= 880), OAC cases with an unascertainable BO status (BO(?) OAC; n= 985), cancer-free BO cases (n=1,091) and reflux controls (n=554). A subset of the OAC cases (n=950) with available clinical, epidemiological and whole-genome sequencing data was also examined.
There was little to no association between most of the 34 clinical and epidemiological factors and the OAC phenotypes. Weak associations were observed for cigarette smoking and gender with self-reported ever-smoking and female cases being more likely in the BO-ve OAC phenotype group relative to the BO+ve OAC phenotype group. However, tumour stage, lymph node spread and metastasis (TNM) was strongly associated with increased risk of BO-ve OAC. Higher TNM stage was strongly correlated with BO-ve OAC with an adjusted odds ratio of 2.4 (95% CI:1.8-3.3), 2.9 (95% CI:2.2-3.9) and 3.2 (95% CI: 1.7-5.9) for stages II, III and IV, compared to stage I. The improved survival associated with BO+ve OAC persisted in survival analyses adjusted for the tumour stage and location as well as the effects of smoking, obesity and heartburn (adjusted hazard ratio=0.88, 95% CI: 0.77-0.95, p=0.015). Of note, the BO-ve OAC phenotype was reported for 21 OAC cases with a history of undergoing endoscopic surveillance for BO.
Seven different types of genomic alterations were examined in relation to the OAC phenotypes. BO+ve OAC tumours had a slightly higher tumour mutation load relative to BO-ve OAC tumours, which was not explained by the effects of ageing and cigarette smoking. There were no differences in the distribution of driver gene alterations, frequency of whole-genome doubling events, or rates of aneuploidy between the OAC phenotypes. Similarly, the prevalence of complex events such as breakage-fusion-bridges and extrachromosomal DNA did not differ according to OAC phenotype. Importantly, signature 17, which is shown to be preserved across the BO-OAC continuum, was equally enriched among the BO+ve OAC and BO-ve OAC tumours.
This thesis presents the first comprehensive evaluation of epidemiological, clinical and molecular factors between the two defined OAC phenotypes. While certain epidemiological factors differ between the phenotypes, they do not explain the observed prognostic difference. The genomic landscapes of these tumour phenotypes were remarkably similar. Taken together, it is likely that all OACs arise from BO even if this precursor lesion is no longer apparent at the time of diagnosis or resection pathology. The advanced-stage tumours suggest that the precursor lesion is overgrown in BO-ve OACs. This work contributes evidence for screening strategies focused on identifying individuals with BO to reduce the public health burden of OAC.