Gene mutations of SWI/SNF complex and molecular profile in colorectal cancer


Ryuma Tokunaga, Joanne Xiu, Curtis Johnston, Richard M. Goldberg, Philip A. Philip, Andreas Seeber, Francesca Battaglin,Hiroyuki Arai,Jae Ho Lo,Alberto Puccini, Madiha Naseem, Martin D. Berger, Shivani Soni, Wu Zhang, Sting Chen, Jimmy J. Hwang, Anthony F. Shields, John L. Marshall, Hideo Baba, W. Michael Korn, Heinz-Josef Lenz


The SWItch/Sucrose Non-Fermentable (SWI/SNF) complex includes proteins produced by 29 genes that regulate chromatin structure remodeling through effects upon transcription, replication, and repair. Understanding how SWI/SNF gene mutations interact to affect cancer progression could lead to new treatment strategies.


We analyzed 7,370 colorectal cancer (CRC) samples with immunohistochemical stains (IHC) and Next-Generation Sequencing (NGS) using a 592-gene panel to examine the association between gene mutations of the SWI/SNF complex (ARID1A, ARID2, PBRM1, SMARCA4, SMARCB1, SMARCE1, BCL11A, BCL11B, BCL7A, SS18, and SS18L1) and molecular features.


The overall mutation rate of the SWI/SNF complex genes was 11.3% (ARID1A: 7.7%, ARID2: 1.7%, SMARCA4: 1.3%, PBRM1: 1.2%, BCL11A: 1.0%, SMARCB1: 0.5%, BCL11B: 0.5%, SMARCE1: 0.3%, SS18: 0.3%, BCL7A: 0.1%, SS18L1: 0.1%). When compared to tumors with SWI/SNF wild-type genes, those tumors with SWI/SNF gene mutations showed significantly higher rates of microsatellite instability (MSI)-high (40.9% vs 2.4%, P < 0.001), tumor mutational burden (TMB)-high (>= 10mut/MB) (56.8% vs 21.6%, P < 0.001) and PD-L1 positivity (17.9% vs 5.5%, P < 0.001). Tumors with each gene mutant also had strong association with the immune profile (MSI-high, TMB-high, and PD-L1 positivity) (Table 1). Furthermore, even SWI/SNF gene mutant samples with microsatellite stable status were significantly associated with TMB-high (28.2%, P < 0.001) and PD-L1 positivity (10.0%, P < 0.001).


Gene mutations of the SWI/SNF complex exhibit findings that suggest that this subgroup of CRCs may have a higher likelihood of response to PD-1 and PD-L1 targeting monoclonal antibodies. If validated in other data sets, these findings can be used to justify clinical trials with eligibility based upon the presence of mutations within the SWI/SNF complex.

Download Publication