A Novel Signature for Predicting Prognosis of Smoking-Related Squamous Cell Carcinoma

Tobacco smoking is an established risk factor for squamous cell carcinoma (SCC). We obtained smoking-related SCC, including cervical SCC (CSCC), esophageal SCC (ESCC), head and neck SCC (HNSC), and lung SCC (LUSC), from The Cancer Genome Atlas (TCGA) database to investigate the association between smoking status (reformed and current smoking) and prognosis. We found that reformed smokers had a better prognosis than current smokers in CSCC (p = 0.003), HNSC (p = 0.019), and LUSC (p < 0.01) cohorts. Then, we selected LUSC cohorts as the training cohort and other SCC cohorts as the test cohorts. Function analysis revealed that homologous recombination (HR) was the most significant pathway involved in smoking-induced LUSC. Moreover, the effect of cross-talk between the smoking status and HR deficiency (HRD) on the prognosis was further evaluated, revealing that quitting smoking with high HRD scores could significantly improve patients' prognosis (p < 0.01). To improve prognosis prediction and more effectively screen suitable populations for platinum drugs and poly-ADP-ribose polymerase (PARP) inhibitors, we constructed a risk score model using smoking- and HRD-related genes in LUSC. The risk score model had high power for predicting 2-, 3-, and 5-year survival (p < 0.01, AUC = 0.67, 0.66, and 0.66). In addition, the risk scores were an independent risk factor for LUSC (HR = 2.34, 95%CI = 1.70-3.23). The practical nomogram was also built using the risk score, smoking status, and other clinical information with a good c-index (0.72, 95%CI = 0.70-0.74). Finally, we used other TCGA SCC cohorts to confirm the reliability and validity of the risk score model (p < 0.01 and AUC > 0.6 at 2, 3, and 5 years in CSCC and HNSC cohorts). In conclusion, the present study suggested that smoking cessation should be a part of smoking-related SCC treatment, and also provided a risk score model to predict prognosis and improve the effectiveness of screening the platinum/PARP population.