Clinicopathological and genomic analysis of SWI/SNF chromatin remodeling abnormalities with a focus on SMARCA4 in cancer of unknown primary.

Purpose: The estimation of the primary site is crucial when considering chemotherapy regimens in cancer of unknown primary (CUP). The task is particularly challenging for poorly differentiated or undifferentiated carcinoma, or unknown histological tumors with unknown primary (U-CUP). Instead of site-specific chemotherapy, a biomarker-guided therapy using genomic testing is required to predict the efficacy of molecular-targeted agents and immune checkpoint inhibitors (ICI). We focused on inactivating the SWI/SNF complex, a chromatin regulatory complex. We investigated the clinical features of CUP with SWI/SNF chromatin remodeling abnormalities and examined whether SWI/SNF chromatin remodeling abnormalities are a predictive marker of ICI efficacy.

Methods: A multi-institutional observational study was conducted between January 2009 and March 2022. Immunostaining for SMARCA2, SMARCA4, and SMARCB1 was performed on 80 patients with CUP. Nextgeneration sequencing analysis was conducted on SMARCA4, SMARCA2, SMARCB1, ARID1A, PBRM1, ARID2, and ARID1B, which are frequent SWI/SNF-associated genes, in 32 patients with CUP.

Results: Immunohistochemistry revealed that the loss of SMARCA4 protein was most frequent, occurring in 14 patients (17.5%). Among the 32 patients with CUP, SMARCA4 mutations were detected in 50% (n = 16) of patients. In 6 cases with truncating mutations, immunostaining revealed protein loss. U-CUP cases were associated with loss of SMARCA4 protein. In SMARCA4-deficient patients, overall survival was prolonged in the ICI-containing regimen group (p = 0.033).

Conclusion: This study demonstrated SWI/SNF chromatin remodeling abnormalities in CUP and the association between SMARCA4 deficiency and U-CUP. It suggests a potential strategy for selecting an ICI regimen for CUP, particularly U-CUP, with SMARCA4 deficiency.