Whole genome sequencing in oesophageal adenocarcinoma unmasks potential precision therapies

Oesophageal adenocarcinoma (OAC) incidence continues to rise in developed countries. Despite advances in deciphering cancer genomes and oncogenic pathways, precision therapies for OAC remain limited. An expansion of precision therapy repertoire in OAC is urgently required.

We assembled 109 actionable and/or potentially actionable genes based on pan-cancer drug information from open-source compendia and clinical trials. To discover approved treatments and potentially targetable alterations (PTAs), we re-analysed whole genome sequencing data of 217 OAC patients and clinically evaluated somatic mutations in these genes using international cancer curation guidelines. Additionally, matching RNA-seq from 210 of the patients was interrogated for select immune checkpoint inhibitor (ICI) targets (n = 59), with expression findings validated in an independent OAC cohort (n = 114).

Approved actionable targets were revealed in 23% of patients; including HER-2 and MET antagonists, and immunotherapy directed by microsatellite instability and high tumour mutation burden. PTAs were noted in a further 72.4% of patients, although the highest frequency was in TP53 which is a challenging target for treatment. Other PTAs were noted in APC, ARID1A, BRCA1, BRCA2, CCNE1, CDKN2A, EGFR, KRAS, MDM2, PIK3CA, PTEN, SMARCB1 and TSC2. Candidate co-occurring alterations included co-occurrence of PTEN loss and ERBB2 amplification and co-occurring variants in KRAS and TP53. For the remaining 4.6% of patients, no PTAs were detected. We identified and validated high expression of four genes encoding candidate ICI targets for OAC: CD24, VEGFA, PVR, and SLC3A2.

These PTAs and ICI targets will help to inform future clinical trials to facilitate precision therapy for patients with OAC.