Correlative assessment of p53 immunostaining patterns and  <i>TP53</i> mutation status by next‐generation sequencing in lung adenocarcinoma ( <scp>LUAD</scp> )

Objectives TP53 mutations, prevalent in 50%–70% of lung adenocarcinoma (LUAD), are associated with poor prognosis and therapeutic resistance. This study aimed to evaluate the diagnostic accuracy of p53 immunohistochemistry (IHC) as a rapid and cost‐effective alternative to next‐generation sequencing (NGS) for TP53 mutation detection in LUAD patients. Materials and methods A multicentre cohort of 221 LUAD patients was analysed. TP53 mutation status was determined via NGS and compared with p53 IHC staining patterns. A multiparametric p53 IHC assessment system was established, integrating staining intensity, spatial distribution and subcellular localization data. Results p53 IHC demonstrated high concordance with TP53 mutation status, achieving an overall accuracy of 91.40% ( κ = 0.83). A novel ≥40% cut‐off for 3+ nuclear staining predicted TP53 mutations with 94.81% accuracy ( κ = 0.91). Complete p53 absence or cytoplasmic expression strongly correlated with truncating mutations (92.31% concordance), while missense mutations were linked to nuclear overexpression. TP53 ‐mutant tumours exhibited distinct molecular profiles, including increased frequencies of RB1 , MET , ERBB2 , MYC and PTCH1 mutations, alongside reduced STK11 comutations. Kaplan–Meier survival analysis demonstrated that p53 IHC serves as a reliable surrogate marker for TP53 mutation status, offering significant prognostic value in LUAD patients. Conclusion p53 IHC, particularly using a ≥40% cut‐off at 3+ intensity, is an accurate and accessible surrogate for TP53 mutation detection in LUAD patients. This method facilitates rapid molecular stratification, optimal resource utilization and informed prognostic and therapeutic decision‐making in routine pathology practice.