Exploiting the weak link: Ataxia-Telangiectasia Mutated dysfunction in oesophagogastric tumours.

Abstract

ATM (ataxia-telangiectasia mutated) is a central regulator of the DNA damage response, coordinating double-strand break repair, checkpoint control, and cell fate decisions. Its disruption drives genomic instability and has been implicated across multiple tumour types. In oesophagogastric cancers, ATM alterations occur in a clinically relevant subset of cases, encompassing both somatic and germline events, and are associated with distinct molecular features including reduced co-occurrence with TP53 mutations and elevated homologous recombination deficiency scores. This narrative review synthesises published literature and publicly available genomic databases to examine ATM biology, the spectrum of ATM alterations across oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, and gastric cancer subtypes, and the challenges of defining true ATM deficiency. The therapeutic implications of ATM dysfunction are evaluated across radiotherapy, platinum-based chemotherapy, ATR inhibition, and PARP inhibition. ATM alterations are detected in approximately 6% of tumours pan-cancer and in up to 10% of oesophagogastric cases. Defining ATM deficiency remains challenging, as immunohistochemistry, next-generation sequencing, and functional assays each carry distinct limitations. ATR inhibition emerges as the most consistently supported therapeutic strategy, with converging preclinical and early clinical evidence across oesophagogastric models. By contrast, available data do not support treating ATM deficiency as equivalent to BRCA-like homologous recombination deficiency, and PARP inhibitor monotherapy has not demonstrated consistent benefit. Prospective validation of functional ATM assays, histology-stratified trial design, and integration of genomic, protein-level, and functional evidence represent key priorities for translating ATM-guided strategies into oesophagogastric cancer practice.