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

Autor: Wei Wei, Fangfang Shi, Yang Xu, Yang Jiao, Ying Zhang, Qiuxiang Ou, Xue Wu, Lingyi Yang, Jinhuo Lai
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Journal of Translational Medicine, Vol 21, Iss 1, Pp 1-15 (2023)
Druh dokumentu: article
ISSN: 1479-5876
DOI: 10.1186/s12967-023-04634-1
Popis: Abstract Background 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. Methods 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 results were validated using an external cohort of 2727 NSCLC patients (including 48 with ATM/ATR pathogenic mutations). Results 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
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