SMARCA2 and SMARCA4 expression in cancer: A tissue microarray study on 14,966 tumors from 134 different tumor types

The two mutually exchangeable ATPases SMARCA2 and SMARCA4 form the two catalytic subunits of a polymorphic family of SWI/SNF complexes. In both normal and malignant cells, they play a regulatory role in numerous essential cellular processes. For example, SWI/SNF affects the regulation of cell differentiation, programmed cell death, DNA repair, chromosome stability, signaling pathway crosstalk and cell metabolism. Topical interest in SMARCA4/SMARCA2 is due to the observation of their synthetic lethal relationship, potentially offering new therapeutic approaches. Targeting SMARCA4 deficient cancer cells with SMARCA2 inhibitors or degraders has resulted in significant growth inhibition in experimental systems and further agents are being tested in early clinical trials. To determine the prevalence of SMARCA2/SMARCA4 expression in cancer, a tissue microarray containing 14,966 samples from 134 different tumor entities and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. SMARCA2 immunostaining was absent in 6.9%, weak in 8.0%, moderate in 18.3%, and strong in 66.8% of 12,253 interpretable tumors. SMARCA4 staining was absent in 0.7%, weak in 1.9%, moderate in 5.9%, and strong in 91.5% of 13,093 interpretable tumors. Remarkably, losses of SMARCA2 and SMARCA4 were strongly correlated. Of 91 SMARCA4 deficient tumors for which SMARCA2 data were also available, 28 (30.8%) did also show a complete loss of SMARCA2 expression. SMARCA2 deficiency was most commonly seen in Burkitt lymphoma (66.7%), endometrial carcinomas (up to 57.1%), rhabdoid tumors (50.0%) and ovarian carcinomas (up to 37.8%). SMARCA4 staining was predominantly lost in in neuroendocrine carcinomas (up to 25.0%), endometrioid carcinomas (up to 7.7%) and adenocarcinomas of the lung (7.5%). Absent or low SMARCA2 expression was significantly linked to unfavorable tumor phenotype in clear cell renal cell carcinoma, bladder cancer, and breast cancer while weak or absent SMARCA4 staining was linked to unfavorable tumor features in colorectal and clear cell renal cell carcinoma (p≤0.05). It is concluded, that SMARCA4 deficiency is a rather rare event in tumors, whereas SMARCA2 deficiency is much more common in many different tumor entities and is associated with unfavourable cancer characteristics in several tumor types. The frequent co-deficiency of SMARCA2 and SMARCA4 challenges the concept of a synthetic lethal relationship of these proteins in vivo.