Molecular Characteristics and Treatment Implications of TP53 Gain-of-Function Mutations in Non-Small Cell Lung Cancer.

BACKGROUND: TP53 gain-of-function (GOF) effects lead to cellular responses beyond the capabilities of wild-type TP53 and are known to promote cancer progression, resulting in poorer outcomes in cancer. METHODS: A total of 486 patients diagnosed with non-small cell lung cancer (NSCLC) with baseline DNA sequencing data were enrolled in our study cohort. In addition, clinical and sequencing data from external NSCLC cohorts, including a cohort with histologic data (N = 219), a combined cohort from two studies treated with immunotherapy (N = 315), and a cohort treated with ROS1 tyrosine kinase inhibitor (TKI) (N = 50), were analyzed to assess the relationships between TP53 GOF mutations and histologic subtypes, immunotherapy outcomes, and ROS1-TKI treatment efficacy. RESULTS: Compared to TP53 non-GOF mutations, patients with TP53 GOF mutations showed higher mutation rates in PIK3CA, STK11, and CTNNB1 but lower in NTRK1; increased VEGFA but decreased DLL3 and HRAS amplification rates. Patients with TP53 GOF mutations exhibited significantly higher tumor mutation burdens compared to those with non-GOF TP53 statuses. Patients with TP53 mutations, both GOF and non-GOF, showed significantly higher expression of immune checkpoints compared to TP53 wild-type patients. GOF-mutated patients also had higher M1 macrophage and CD8+ T cell infiltration, along with elevated B cell receptor signaling. Consistent with our findings, analysis of external cohorts revealed that TP53 GOF mutations were associated with improved prognosis in the context of immunotherapy. Among ROS1 fusion-positive patients treated with ROS1-TKIs, those harboring TP53 GOF mutations had a longer median PFS compared to patients with non-GOF TP53, although both were shorter than those with wild-type TP53. Additionally, TP53 GOF mutations were associated with a relatively lower histologic grade than non-GOF mutations. CONCLUSIONS: TP53 GOF mutations were associated with poorer ROS1-TKI treatment outcomes but improved immunotherapy response in NSCLC, with elevated immune activities and distinct molecular profiles.