Genetic progression of Barrett's oesophagus to oesophageal adenocarcinoma

Abstract

Barrett's oesophagus (BE) is the premalignant condition associated with the development of oesophageal adenocarcinoma (OAC). Diagnostically, p53 immunohistochemistry remains the only biomarker recommended clinically to aid histopathological diagnosis. The emerging mutational profile of BE is one of highly heterogeneous lesions at the genomic level with many mutations already occurring in non-dysplastic tissue. As well as point mutations, larger scale copy-number changes appear to have a key role in the progression to OAC and clinically applicable assays for the reliable detection of aneuploidy will be important to incorporate into future clinical management of patients. For some patients, the transition to malignancy may occur rapidly through a genome-doubling event or chromosomal catastrophe, termed chromothripsis, and detecting these patients may prove especially difficult. Given the heterogeneous nature of this disease, sampling methods to overcome inherent bias from endoscopic biopsies coupled with the development of more objective biomarkers than the current reliance on histopathology will be required for risk stratification. The aim of this approach will be to spare low-risk patients unnecessary procedures, as well as to provide endoscopic therapy to the patients at highest risk, thereby avoiding the burden of incurable metastatic disease.

Figure 1

Algorithm for the clinical management of patients with diagnosis of Barrett's oesophagus. Displayed is a summary of the currently recommended algorithm for surveillance and treatment of patients with Barrett's oesophagus according to the latest BSG guidelines. Patients with non-dysplastic Barrett's oesophagus should be included in endoscopic surveillance programmes at clearly defined intervals, apart from patients with short-segment Barrett's and only gastric metaplasia, which can be considered for discharge from surveillance. Patients with HGD and more advanced lesions should be discussed for therapeutic intervention at the local MDT. Patients with LGD need short-term follow up for confirmation. If the degree of dysplasia is confirmed by two independent pathologist treatment can also be discussed at the local MDT. EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; HGD, high-grade dysplasia; LGD, low-grade dysplasia; MDT, multidisciplinary team meeting; OAC, oesophageal adenocarcinoma; RFA, radio frequency ablation.

Figure 2

Genetic events in the progression of Barrett's oesophagus. (A) Illustration of progression to oesophageal adenocarcinoma (OAC) from multiple clones with accumulation of mutations, with a predominance of tumour suppressor genes over time. CDKN2A loss of function is shown as an early event, p53 mutation likely to mark the boundary to dysplasia and SMAD4 mutations seen uniquely in the cancer. Copy-number changes, structural variants and genetic instability increase over time. A crisis event (denoted by *) may occur to promote rapid genomic instability and progression to cancer. Neutral clones may regress over time (e.g., grey and purple clones). (B) A diagram to show issues with sampling bias in a segment of Barrett's over time. Regions of the Barrett's lesion harbouring example mutations are highlighted. Heterogeneity within an individual segment of Barrett's means that endoscopic samples may be from tissue containing all, some or none of the mutations present in the entire lesion. No dysplasia is denoted by the blue dashed line and high-grade dysplasia (HGD) or oesophageal adenocarcinoma (OAC) in orange and pink, respectively. Even in regions described histologically as HGD and OAC, different combinations of mutations may be seen depending on sampling. For example, in panel 2, sequencing of sample 1 would show a CDKN2A mutation, sample 2 a p53 mutation and sample 3 would exhibit both mutations.