Background: Lung cancer (LC) is the second leading causes of cancer-related mortality and composed of diverse molecular types. Tumor suppressor gene TP53 is one of the most frequency mutation genes in cancer, however, whether there are the hot sports of TP53 mutations has always been a challenging issue. The aim of this study was to explore the spectrums and hot spots of TP53 mutation in LC. Methods: The total 1932 LC tissue samples (from same number of patients，all cases had patients' informed consent) in formalin fixed and paraffin embedded were collected from Guangzhou Huayin Health Medical Group Co.,Ltd. By targeting next generation sequencing (NGS) of 600 genes, the mutation information of TP53 and other genes was obtained. Results: Among 1932 samples, 1025(53%) were male, 1685(87.2%) were lung adenocarcinoma (LUAD), 232(12.0%) were lung squamous cell carcinoma (LSCC), 7(0.4%) were large-cell carcinoma and 8(0.4%) were small-cell carcinoma, median age was 62.82(range: 27-92). The mutated TP53 was detected in 890 (46%) samples. Other most frequently altered genes were EGFR (1114/1932, 57%), KRAS (213/1932, 11%), PIK3CA (116/1932, 6%), APC (107/1932, 6%) and ERBB2 (97/1932, 5%). Additionally, 412 (21.3%) patients with TP53 and EGFR co-mutation, TP53 and KRAS co-mutation occurred in 81 (4.2%) patients, PIK3CA mutation co-occurred with TP53 in 53 (2.7%) patients. The total of 920 TP53 mutant sites were detected, and these sites scattered throughout the 11 exons, especially exon 5-8. 13 of these mutation sites which accounted as high frequency ( > 10), including R273C (18/920), R248W (16/920), Y220C (15/920), Y163C (14/920), R249S (13/920), R282W (13/920), H179R (12/920), R158L (12/920), R175H (11/920), G245D (11/920), R273H (10/920), Y234C (10/920), and R273L (10/902). In addition, missense mutations were the main type, and the proportion of SNP with C > T was the highest in mutation sites. Conclusions: This study characterized the mutational signatures that TP53 mutations are interspersed, and hot spots are just in small proportions in LC. This study may provide a basis for drug development for targeting TP53 mutations in the future.