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

作者：Kristina Mardinian, Jacob J. Adashek, Gregory P. Botta, Shumei Kato, Razelle Kurzrock · 发表于：Molecular Cancer Therapeutics · 年份：2021 · DOI：10.1158/1535-7163.mct-21-0433 · 被引用次数：184 · 研究领域：Chromatin Remodeling and Cancer、Protein Degradation and Inhibitors、Mechanisms of cancer metastasis

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...