Integrated epidemiogical and genomic data yields insights into the relationship between precancer and cancer states of the oesophagus

Cancer generally takes years to evolve, and early diagnosis can prevent life-threatening cancer^1,2. Symptomatic, advanced cancers often lack evidence of a precancer at diagnosis and yet, if the link between a precancerous state and cancer can be proven, the opportunity arises for screening and prevention. Oesophageal adenocarcinoma (EAC) is an increasingly prevalent,³ poor outcome cancer and its presumed precursor, Barrett’s oesophagus (BE) is only evident in around half of cases^4,5. To test the hypothesis that BE is not a pre-requisite to EAC we classified a prospective cohort of 3,100 EAC patients for any evidence of BE and compared the epidemiological, clinical and genomic characteristics. Our findings demonstrate that there are specific demographic and genomic features observed in BE that also correlate strongly with EAC, regardless of the presence of a BE phenotype. Further we found evidence for the earliest features of BE evolution in both BE-negative and BE-positive EAC phenotypes. Advanced tumour stage was the only variable that corresponded with increased likelihood of BE-negative EAC, including in some patients with a prior diagnosis of Barrett’s. The role of a single BE-mediated pathway to EAC has implications for early diagnosis strategies. We anticipate that our methodology combining large epidemiological and genomic datasets with respect to phenotype could help establish the significance of other precancer states.