Mutational and Transcriptional Characterization Establishes Prognostic Models for Resectable Lung Squamous Cell Carcinoma

BACKGROUND: The prognosis of non-small cell lung cancer (NSCLC) patients has been comprehensively studied. However, the prognosis of resectable (stage I–IIIA) lung squamous cell carcinoma (LUSC) has not been thoroughly investigated at genomic and transcriptional levels. METHODS: Data of genomic alterations and transcriptional-level changes of 355 stage I–IIIA LUSC patients were downloaded from The Cancer Genome Atlas (TCGA) database, together with the clinicopathological information (training cohort). A validation cohort of 91 patients was retrospectively recruited. Data were analyzed and figures were plotted using the R software. RESULTS: Training cohort was established with 355 patients. TP53 (78%), TTN (68%), CSMD3 (39%), MUT16 (36%) and RYR2 (36%) were genes with the highest mutational frequency. BRINP3, COL11A1, GRIN2B, MUC5B, NLRP3 and TENM3 exhibited significant higher mutational frequency in stage III (P < 0.05). Patients with stage III also exhibited significantly higher tumor mutational burden (TMB) than those with stage I (P < 0.01). The mutational status of 10 genes were found to have significant stratification on patient prognosis. TMB at threshold of 25 percentile (TMB = 2.39 muts/Mb) also significantly stratified the patient prognosis (P = 0.0003). Univariate and multivariate analyses revealed TTN, ADGRB3, MYH7 and MYH15 mutational status and TMB as independent risk factors. Further analysis of transcriptional profile revealed many significantly up- and down-regulated genes, and multivariate analysis found the transcriptional levels of seven genes as independent risk factors. Significant factors from the multivariate analyses were used to establish a Nomogram model to quantify the risk in prognosis of individual LUSC patients. The model was validated with a cohort containing 91 patients, which showed good predicting efficacy and consistency. CONCLUSION: The influencing factors of prognosis of stage I–III LUSC patients have been revealed. Risk factors including gender, T stage, cancer location, and the mutational and transcriptional status of several genes were used to establish a Nomogram model to assess the patient prognosis. Subsequent validation proved its effectiveness.