Clinicopathologic, genomic, and immunophenotypic landscape of ATM mutations in non-small cell lung cancer Journal Article

   


Authors: Ricciuti, B.; Elkrief, A.; Alessi, J.; Wang, X.; Li, Y.; Gupta, H.; Muldoon, D. M.; Bertram, A. A.; Pecci, F.; Lamberti, G.; Di Federico, A.; Barrichello, A.; Vaz, V. R.; Gandhi, M.; Lee, E.; Shapiro, G. I.; Park, H.; Nishino, M.; Lindsay, J.; Felt, K. D.; Sharma, B.; Cherniack, A. D.; Rodig, S.; Gomez, D. R.; Shaverdian, N.; Rakaee, M.; Bandlamudi, C.; Ladanyi, M.; Jänne, P. A.; Schoenfeld, A. J.; Sholl, L. M.; Awad, M. M.; Cheng, M. L.
Article Title: Clinicopathologic, genomic, and immunophenotypic landscape of ATM mutations in non-small cell lung cancer
Abstract: 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, inser-tions/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 concurrentATM/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 immunophe-notypic features. Our data may serve as resource to guide inter-pretation of specific ATM mutations in NSCLC.
Keywords: assay; inhibition
Journal Title: Clinical Cancer Research
Volume: 29
Issue: 13
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2023-07-01
Start Page: 2540
End Page: 2550
Language: English
ACCESSION: WOS:001027431800001
DOI: 10.1158/1078-0432.Ccr-22-3413
PROVIDER: wos
PUBMED: 37097610
PMCID: PMC11031845
Notes: Article -- Source: Wos
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MSK Authors
  1. Daniel R Gomez
    237 Gomez
  2. Marc Ladanyi
    1326 Ladanyi
  3. Chaitanya Bandlamudi
    78 Bandlamudi
  4. Adam Jacob Schoenfeld
    131 Schoenfeld
  5. Narek Shaverdian
    98 Shaverdian
  6. Arielle Elkrief
    41 Elkrief
  7. Daniel Martin Muldoon
    4 Muldoon
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