ATM Immunohistochemistry as a Tool to Identify and Classify Somatic ATM Variants in Prostate Cancer

Background/Objectives: Ataxia telangiectasia-mutated kinase is encoded by the ATM gene. This gene is altered in many cancer types; however, it is most relevant for eligibility of poly-ADP-ribose polymerase inhibitor (PARPi) therapy in metastatic castrate-resistant prostate cancer in Canada. Non-benign ATM alterations are relatively uncommon, seen in less than 10% of prostate cancers; however, many of these are variants of uncertain significance with limited evidence of clinical significance or actionability. Methods: To aid in variant classification of next-generation sequencing results, ATM immunohistochemistry (IHC) is performed on patient tumour samples to serve as patient-specific functional evidence for ATM protein loss. Results: ATM IHC demonstrates strong concordance with known loss-of-function variants and copy number losses. Additionally, it can be used to clarify ATM protein loss in cases involving variants of uncertain significance (VUSs) or copy number deletions. Conclusions: Incorporation of ATM IHC into clinical testing for prostate cancer represents a relatively cost-effective orthogonal approach that can rescue poor-quality NGS results and clarify the functional impact of ATM VUSs on protein expression. Overall, this strategy may provide useful supportive evidence in prostate cancer biomarker testing and interpretation.