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Updated: Aug 1, 2025
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non-Small Cell Lung Cancer
Biagio Ricciuti1, Arielle Elkrief2, Joao Alessi1
1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Purpose:
ATM is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC); however, limited characterization has been pursued.
Experimental Design:
Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM 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. ATM-mutant (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 with ATM-wild-type (ATMWT) cases. Among 3,687 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 with tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N = 1,522) 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.
Conclusions:
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.
Insights
ATM gene mutations are common in non-small cell lung cancer (NSCLC). These ATM-mutant NSCLCs have distinct features, but similar responses to immunotherapy, except when combined with TP53 mutations.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- ATM is the most frequently mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC).
- Limited characterization of ATM mutations and their clinical implications in NSCLC has been performed.
Purpose of the Study:
- To characterize the clinicopathologic, genomic, and immunophenotypic features of ATM-mutant NSCLC.
- To investigate the association of ATM mutations with co-occurring genomic alterations and response to cancer therapies.
Main Methods:
- Genomic profiling of 5,172 NSCLC patients.
- ATM immunohistochemistry (IHC) on 182 NSCLC samples with ATM mutations.
- Multiplexed immunofluorescence on 535 samples to analyze immune cell infiltration.
Main Results:
- Deleterious ATM mutations were identified in 9.7% of NSCLC cases, associated with female sex, ever smoking, non-squamous histology, and higher tumor mutational burden.
- ATM-mutant NSCLC showed enrichment of KRAS, STK11, and ARID2 mutations, while ATM-wild-type NSCLC had enriched TP53 and EGFR mutations.
- ATM mutations correlated with ATM loss by IHC, but clinical outcomes to PD-(L)1 monotherapy and chemo-immunotherapy were similar between ATM-mutant and wild-type NSCLC, except for improved response in ATM/TP53 co-mutant cases.
Conclusions:
- Deleterious ATM mutations define a distinct NSCLC subset with unique molecular and clinical features.
- ATM mutation status, particularly in conjunction with TP53, may inform treatment strategies for NSCLC patients receiving immunotherapy.
