SMARCA4: Implications of an Altered Chromatin-Remodeling Gene for Cancer Development and Therapy

Abstract

The SWI/SNF chromatin remodeling complex, via nucleosome topology modulation, regulates transcription. The SMARCA4 (BRG1) subunit codes for the ATPase energy engine of the SWI/SNF complex. SMARCA4 is a tumor suppressor that is aberrant in ∼5% to 7% of human malignancies. Class I SMARCA4 alterations (truncating mutations, fusions, and homozygous deletion) lead to loss of function whereas class II alterations (missense mutations) have a dominant negative/gain-of-function effect and/or loss-of function. SMARCA4 alterations typify the ultra-rare small cell carcinomas of the ovary hypercalcemic type (SCCOHT) and SMARCA4-deficient thoracic and uterine sarcomas; they are also found in a subset of more common tumors, for example, lung, colon, bladder, and breast carcinomas. Germline variants in the SMARCA4 gene lead to various hereditary conditions: rhabdoid tumor predisposition syndrome-2 (RTPS2), characterized by loss-of-function alterations and aggressive rhabdoid tumors presenting in infants and young children; and Coffin-Siris syndrome, characterized by dominant negative/gain-of function alterations and developmental delays, microcephaly, unique facies, and hypoplastic nails of the fifth fingers or toes. A minority of rhabdoid tumors have a germline SMARCA4 variant as do >40% of women with SCCOHT. Importantly, immune checkpoint blockade has shown remarkable, albeit anecdotal, responses in SCCOHT. In addition, there is ongoing research into BET, EZH2, HDAC, CDK4/6, and FGFR inhibitors, as well as agents that might induce synthetic lethality via DNA damage repair impairment (ATR inhibitors and platinum chemotherapy), or via the exploitation of mitochondrial oxidative phosphorylation inhibitors or AURKA inhibitors, in SMARCA4-aberrant cancers.