The enrichment of Fanconi anemia/homologous recombination pathway aberrations in ATM/ATR-mutated NSCLC was accompanied by unique molecular features and poor prognosis

ATM and ATR are two critical factors to regulate DNA damage response (DDR), and their mutations were frequently observed in different types of cancer, including non-small cell lung cancer (NSCLC). Given that the majority of identified ATM/ATR mutations were variants of uncertain significance, the clinical/molecular features of pathogenic ATM/ATR aberrations have not been comprehensively investigated in NSCLC.

Our results demonstrated the unique clinical and molecular features of pathogenic ATM/ATR mutations in NSCLC, which helps better understand the cancerous involvement of these DDR regulators, as well as directing targeted therapies and/or immunotherapies to treat ATM/ATR-mutated NSCLC, especially those with co-existing FA/HR aberrations.

Next-generation sequencing (NGS) analyses were conducted to investigate the molecular features in 191 NSCLC patients who harbored pathogenic/likely pathogenic ATM/ATR mutations and 308 NSCLC patients who did not have any types of ATM/ATR variants. The

Most pathogenic ATM/ATR genetic alterations were frameshift and nonsense mutations that disrupt critical domains of the two proteins. ATM/ATR-mutated patients had significantly higher tumor mutational burdens (TMB; P < 0.001) and microsatellite instabilities (MSI; P = 0.023), but not chromosomal instabilities, than those without any ATM/ATR variations. In particular, KRAS mutations were significantly enriched in ATM-mutated patients (P = 0.014), whereas BRCA2 mutations (P = 0.014), TP53 mutations (P = 0.014), and ZNF703 amplification (P = 0.008) were enriched in ATR-mutated patients. Notably, patients with ATM/ATR pathogenic genetic alterations were likely to be accompanied by mutations in Fanconi anemia (FA) and homologous recombination (HR) pathways, which were confirmed using both the study (P < 0.001) and validation (P < 0.001) cohorts. Furthermore, the co-occurrence of FA/HR aberrations could contribute to increased TMB and MSI, and patients with both ATM/ATR and FA/HR mutations tended to have worse overall survival. Conclusions: Our results demonstrated the unique clinical and molecular features of pathogenic ATM/ATR mutations in NSCLC, which helps better understand the cancerous involvement of these DDR regulators, as well as directing targeted therapies and/or immunotherapies to treat ATM/ATR-mutated NSCLC, especially those with co-existing FA/HR aberrations.