Usefulness of BRG1 immunostaining in detecting SMARCA4 deficiency in “so-called” cancers of unknown primary in daily pathology practice

SMARCA4 encodes BRG1, loss of which is associated with aggressive tumor biology. Although SMARCA4 deficiency has been described in various malignancies, its role in “so-called” cancers of unknown primary (“so-called” CUP), that is, metastatic tumors encountered in pathology practice without a clear primary site, remains unclear. We retrospectively studied 108 cases submitted as so-called “CUP” between 2017 and 2023, in which the primary site could not be determined at the time of diagnosis. Histological features and BRG1 immunohistochemistry were reviewed. BRG1 loss was defined as complete absence of nuclear staining in tumor cells. Comprehensive genomic profiling (CGP) was performed in selected cases with sufficient residual tissue. Tumor mutation burden (TMB) ≥ 10 mutations/Mb was defined as TMB-high. BRG1 loss was observed in 13 tumors (12%). BRG1-loss tumors were significantly more likely to involve the thoracic cavity (85% vs. 36%; p < 0.001) and exhibited prominent necrosis, higher mitotic counts, and nuclear inclusions compared with BRG1-preserved tumors. All nine BRG1-loss tumors tested by CGP harbored pathogenic SMARCA4 mutations, and 78% (7/9 cases) were TMB-high compared with 14% (1/7 cases) of BRG1-preserved tumors. PD-L1 positivity was detected in one of 11 BRG1-loss cases tested. Other mutations observed in BRG-1 loss tumors were not distinctive enough to indicate the primary site. BRG1 immunostaining is a sensitive surrogate of SMARCA4 deficiency in “so-called” CUP. Although BRG1 status does not reliably identify the site of origin, it highlights tumors enriched for thoracic involvement and TMB-high status. These findings support the use of BRG1 as a practical screening tool to select cases for further genomic testing and therapeutic stratification, including potential consideration of immune checkpoint inhibitors.