Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Abstract

Introduction: ATM is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC), however limited characterization has been pursued. Methods: Clinicopathologic, genomic, and treatment data were collected for 5172 patients with NSCLC tumors which underwent genomic profiling. ATM immunohistochemistry (IHC) was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets. Results: A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATMMUT NSCLC was significantly associated with female sex (P=0.02), ever smoking status (P<0.001), non-squamous histology (P=0.004) and higher tumor mutational burden (DFCI: P<0.0001; MSK: P<0.0001) compared to ATMWT cases. Among 3687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q<0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs 28.6%, P<0.0001) compared to tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N=1522) and chemo-immunotherapy (N=951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy. Conclusion: Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.

ATM—the gene at the moment in non-small cell lung cancer

“…However, besides establishing that germline ATM variants are associated with increased lung cancer susceptibility, the clinical significance of somatic ATM mutations in NSCLC has not been robustly defined. Addressing this knowledge gap, Ricciuti et al recently published a study characterizing ATM mutations in NSCLC which was followed by a similar study led by Vokes and colleagues ( 10 , 11 ). Here, we briefly summarize the findings of these studies and share our perspective on pertinent questions that should be considered when interpreting the clinical relevance of ATM mutations as biomarkers for NSCLC.…”

“…Ricciuti and colleagues characterized ATM gene variants in 5,172 tumors from NSCLC patients using either the OncoPanel (tumor-only) or MSK-IMPACT (tumor and normal tissue) NGS panels, and identified deleterious ATM mutations in 9.7% of cases ( 10 ). ATM mutations were positively associated with female sex, smoking history, non-squamous histology, TMB and PD-L1 positivity.…”

“…In an attempt to understand the phenotypic consequences of the various ATM mutations identified, both groups examined associations between mutations and protein expression using immunohistochemistry (Ricciuti) or data from reverse-phase protein arrays (Vokes) ( 10 , 11 ). As expected, ATM expression was lower in tumors with truncating mutations (nonsense, frameshift, or indels) compared to missense mutations.…”

“…The functional impact of these “truncating” mutations is also evident from the cancer predisposition of individuals with A-T syndrome who carry them ( 3 ). However, multiple studies have established that most ATM variants in NSCLC are missense mutations, for which functional consequences are more challenging to predict ( 10 , 11 ). This makes missense ATM mutations difficult to interpret with respect to their biological significance and associated clinical relevance.…”

“…NSCLC with ATM mutations apparently have better outcomes after treatment with ICI ( 10 , 11 , 13 , 14 ), indicating that ATM might influence anti-tumor immune responses. This association could simply be explained by the positive correlation between ATM mutation and TMB, which itself has been linked to enhanced tumor immunogenicity and subsequently, susceptibility to anti-tumor immunity ( 3 ).…”