SWI/SNF Complex Genomic Alterations as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Multiple Cancers
Di Wang, Jianchao Wang, Dongmei Zhou, Zhixian Wu, Wei Liu, Yanping Chen, Gang Chen, Jing Zhang
Abstract
Whether there is an association between SWI/SNF genomic alterations in tumors and response to immune checkpoint inhibitors (ICI) remains unclear because prior studies have focused on either an individual gene or a predefined set of genes. Herein, using mutational and clinical data from 832 ICI-treated patients who underwent whole-exome sequencing, including sequencing of all 31 genes of the SWI/SNF complex, we found that SWI/SNF complex alterations were associated with significantly improved overall survival (OS) in melanoma, clear-cell renal cell carcinoma, and gastrointestinal cancer, as well as improved progression-free survival (PFS) in non-small cell lung cancer. Including tumor mutational burden as a variable, the multivariate Cox regression analysis showed SWI/SNF genomic alterations had prognostic value in melanoma [HR, 0.63 (95% confidence interval, CI, 0.47-0.85), P = 0.003], clear-cell renal cell carcinoma [HR, 0.62 (95% CI, 0.46-0.85), P = 0.003], and gastrointestinal cancer [HR, 0.42 (95% CI, 0.18-1.01), P = 0.053]. Furthermore, we used the random forest method for variable screening, identifying 14 genes as a SWI/SNF signature for potential clinical application. Significant correlations were observed between SWI/SNF signature alterations and improved OS and PFS in all cohorts. This suggests that SWI/SNF gene alterations are associated with better clinical outcomes in ICI-treated patients and may serve as a predictive marker for ICI therapy in multiple cancers.