Aims: The incidence of oesophageal adenocarcinoma (OAC) is rising in Australia. With a 5-year survival rate of 14%, the improved diagnostic biomarkers and therapeutic targets are crucial needs. We aimed to identify genomic and transcriptomic features associated with clinical outcome and to characterise relationship between genome and transcriptome in OAC tumours.
Methods: Here, we performed whole genome sequencing and/or RNA sequencing of 115 OAC tumours from patients, most of whom were part of the AGITG DOCTOR clinical trial, to better understand correlation of molecular features and patients’ outcome. We applied computational approaches with the aim to identify previously unidentified events correlated with OAC outcome.
Results: Consistent with previous reports, we observed genomic instability, high number of structural variations and high proportion of copy number alterations in OAC genome. Catastrophic genomic events including chromothripsis, breakage-fusion-bridge (BFB) were common in OAC tumours. The simultaneous presence of other complex events such as kataegis hypermutation were observed in patients with poorer survival. Strikingly, transcriptomic analysis revealed OAC tumour immune subgroups: ‘immune hot’, ‘immune cold’ and ‘immune resistant’, which significantly showed different clinical outcomes. We also investigated genomes of tumour subgroups to find responsible driver event for different immune responses in OAC subgroups.
Conclusion: In this study, we analysed genome and transcriptome profiles of OAC tumours along with clinical data and showed complex genomic events and immune subgroups were associated with patient clinical outcome. Our findings introduce insights for diagnostic biomarkers and therapeutic targets and suggest precision immunotherapy for OAC patients who are not classified as ‘immune resistant’ in future.