Journal Article

SWI/SNF complex gene variations are associated with a higher tumor mutational burden and a better response to immune checkpoint inhibitor treatment: a pan-cancer analysis of next-generation sequencing data corresponding to 4591 cases

Zhu, Weijie, He, Caiyun, Xu, Yuxia, Li, Yue, Wang, Fang, Ma, Jiangjun, Yang, Xinhua

2022

Overview

Background Genes related to the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex are frequently mutated across cancers. SWI/SNF-mutant tumors are vulnerable to synthetic lethal inhibitors. However, the landscape of SWI/SNF mutations and their associations with tumor mutational burden (TMB), microsatellite instability (MSI) status, and response to immune checkpoint inhibitors (ICIs) have not been elucidated in large real-world Chinese patient cohorts. Methods The mutational rates and variation types of six SWI/SNF complex genes ( ARID1A , ARID1B , ARID2 , SMARCA4 , SMARCB1 , and PBRM1 ) were analyzed retrospectively by integrating next-generation sequencing data of 4591 cases covering 18 cancer types. Thereafter, characteristics of SWI/SNF mutations were depicted and the TMB and MSI status and therapeutic effects of ICIs in the SWI/SNF-mutant and SWI/SNF-non-mutant groups were compared. Results SWI/SNF mutations were observed in 21.8% of tumors. Endometrial (54.1%), gallbladder and biliary tract (43.4%), and gastric (33.9%) cancers exhibited remarkably higher SWI/SNF mutational rates than other malignancies. Further, ARID1A was the most frequently mutated SWI/SNF gene, and ARID1A D1850fs was identified as relatively crucial. The TMB value, TMB-high (TMB-H), and MSI-high (MSI-H) proportions corresponding to SWI/SNF-mutant cancers were significantly higher than those corresponding to SWI/SNF-non-mutant cancers (25.8 vs. 5.6 mutations/Mb, 44.3% vs. 10.3%, and 16.0% vs. 0.9%, respectively; all p  < 0.0001). Furthermore, these indices were even higher for tumors with co-mutations of SWI/SNF genes and MLL2/3 . Regarding immunotherapeutic effects, patients with SWI/SNF variations showed significantly longer progression-free survival (PFS) rates than their SWI/SNF-non-mutant counterparts (hazard ratio [HR], 0.56 [95% confidence interval {CI} 0.44–0.72]; p < 0.0001), and PBRM1 mutations were associated with relatively better ICI treatment outcomes than the other SWI/SNF gene mutations (HR, 0.21 [95% CI 0.12–0.37]; p  = 0.0007). Additionally, patients in the SWI/SNF-mutant + TMB-H (HR, 0.48 [95% CI 0.37–0.54]; p  < 0.0001) cohorts had longer PFS rates than those in the SWI/SNF-non-mutant + TMB-low cohort. Conclusions SWI/SNF complex genes are frequently mutated and are closely associated with TMB-H status, MSI-H status, and superior ICI treatment response in several cancers, such as colorectal cancer, gastric cancer, and non-small cell lung cancer. These findings emphasize the necessity and importance of molecular-level detection and interpretation of SWI/SNF complex mutations.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Biliary tract / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Cell Biology / Chromatin remodeling / Clinical medicine / Colorectal cancer / Endometrial cancer / Endometrium / Gastric cancer / Genes / Immune checkpoint inhibitors / Kinases / Lung cancer / Malignancy / Microsatellite instability / Mutants / Mutation / Mutational landscape / Next-generation sequencing / Non-small cell lung carcinoma / Patients / Small cell lung carcinoma / Software / Sucrose / SWI/SNF complex / SWI/SNF complex genes / Synthetic lethality / Tumor mutational burden / Tumors / Variation