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

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• ATM (ataxia-telangiectasia mutated) is a key DNA damage response regulator.
• ATM alterations drive genomic instability and are implicated in various cancers, including oesophagogastric (OG) types.
• These alterations, somatic or germline, define a subset of OG cancers with unique molecular profiles.

Purpose of the Study:

• To review ATM biology and its alterations in oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, and gastric cancer.
• To explore the challenges in defining true ATM deficiency.
• To evaluate therapeutic implications of ATM dysfunction in OG cancers.

Main Methods:

• Narrative review of published literature.
• Analysis of publicly available genomic databases.
• Evaluation of ATM alterations in oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, and gastric cancer subtypes.

Main Results:

• ATM alterations occur in ~6% of pan-cancers and up to 10% of OG cancers.
• Defining ATM deficiency is challenging due to limitations in IHC, NGS, and functional assays.
• ATR inhibition shows consistent preclinical and early clinical support in OG models.

Conclusions:

• ATM deficiency is not equivalent to BRCA-like homologous recombination deficiency; PARP inhibitor monotherapy lacks consistent benefit.
• ATR inhibition is the most promising therapeutic strategy for ATM-altered OG cancers.
• Priorities include validating functional ATM assays and integrating multi-level evidence for clinical translation.