Abstract
Genomic studies performed in cancer patients and tumor-derived cell lines have identified a high frequency of alterations in components of the mammalian switch/sucrose non-fermentable (mSWI/SNF or BAF) chromatin remodeling complex, including its core catalytic subunit, SMARCA4. Cells exhibiting loss of SMARCA4 rely on its paralog, SMARCA2, making SMARCA2 an attractive therapeutic target. Here we report the genomic profiling of solid tumors from 131,668 cancer patients, identifying 9434 patients with one or more SMARCA4 gene alterations. Homozygous SMARCA4 mutations were highly prevalent in certain tumor types, notably non-small cell lung cancer (NSCLC), and associated with reduced survival. The large sample size revealed previously uncharacterized hotspot missense mutations within the SMARCA4 helicase domain. Functional characterization of these mutations demonstrated markedly reduced remodeling activity. Surprisingly, a few SMARCA4 missense variants partially or fully rescued paralog dependency, underscoring that careful selection criteria must be employed to identify patients with inactivating, homozygous SMARCA4 missense mutations who may benefit from SMARCA2-targeted therapy.
Highlights
Genomic studies performed in cancer patients and tumor-derived cell lines have identified a high frequency of alterations in components of the mammalian switch/sucrose nonfermentable chromatin remodeling complex, including its core catalytic subunit, SMARCA4
A subset of SMARCA4-deficient tumors were found to be sensitive to EZH2 inhibition, the catalytic subunit of Polycomb repressive complex (PRC)-2, with SMARCA2 expression potentially serving as a biomarker of insensitivity[20]
More than half the mutations were missense (Fig. 1b), consistent with the spectrum of mutations described from The Cancer Genome Atlas (TCGA) and other pan-cancer analyses[5,6,7,8]
Summary
Genomic studies performed in cancer patients and tumor-derived cell lines have identified a high frequency of alterations in components of the mammalian switch/sucrose nonfermentable (mSWI/SNF or BAF) chromatin remodeling complex, including its core catalytic subunit, SMARCA4. Some indications like NSCLC and cancer of unknown primary (CUP) have a high prevalence of homozygous SMARCA4 mutations with >40% representing truncating alterations suggesting clear loss-of-function (Fig. 1c).
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