Ryanodine receptor (RYR) mutational status correlates with tumor mutational burden, age and smoking status and stratifies non-small cell lung cancer patient prognosis

Background: The ryanodine receptors (RYRs) have been implicated in many muscular, cardiac and neurological diseases. However, there are almost no studies so far focusing on RYR genetic alterations and its roles in cancer, especially in non-small cell lung cancer (NSCLC). Methods: The whole-exome sequencing (WES) data, demographic and clinical data of 1,052 NSCLC patients was downloaded from The Cancer Genome Atlas (TCGA) database and analyzed using the corresponding packages of the R software. Mutational profile was established and its correlation with tumor mutational burden (TMB), prognosis, age and smoking status was analyzed and compared. Results: RYR mutations were found in 502 NSCLC patients, in which mutations of RYR1, RYR2 and RYR3 were found in 17.3% (182/1,052), 40.0% (421/1,052) and 21.3% (224/1,052) of patients, respectively. Random distribution of mutations without hotspot mutations were observed with all three RYR isoforms. Significant co-mutations were found between RYR1 and RYR3, while mutual exclusive mutations were found between RYR1 and RYR2, and between RYR2 and RYR3. Significant correlation was found between cumulative number of mutations and cumulative TMB for all three RYR isoforms, and patients with RYR mutations exhibited significantly higher TMB than those without RYR mutations. Significant correlation was also found between mutational status and age in RYR2 and RYR3, and between mutational status and smoking history grading in all three isoforms, and between mutational status and number of pack years in RYR3. More interestingly, significant stratification of patient survival was revealed by RYR2 mutational status, which was found to be one of the independent risk factors for patient prognosis in multivariate Cox analysis. Conclusions: The mutational profile of RYR in NSCLC has been characterized for the first time. Strong correlation was found between RYR mutational status and TMB, age and smoking status. RYR2 mutational status was an independent risk factor for NSCLC patient prognosis.