1. Impact of Mutations in Subunit Genes of the Mammalian SWI/SNF Complex on Immunological Tumor Microenvironment.
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CHIKAKO HOZUMI, AKIRA IIZUKA, TOMOATSU IKEYA, HARUO MIYATA, CHIE MAEDA, TADASHI ASHIZAWA, TAKESHI NAGASHIMA, KENICHI URAKAMI, YUJI SHIMODA, KEIICHI OHSHIMA, KOJI MURAMATSU, TAKASHI SUGINO, AKIO SHIOMI, YASUHISA OHDE, ETSURO BANDO, KENICHIRO FURUKAWA, TEIICHI SUGIURA, TAKASHI MUKAIGAWA, SEIICHIRO NISHIMURA, and YASUYUKI HIRASHIMA
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TUMOR microenvironment ,MYC oncogenes ,SOMATIC mutation ,GENE expression ,CANCER genes - Abstract
Background/Aim: Recently, inactivating somatic mutations of SWI/SNF chromatin-remodeling genes in cancers have been reported. However, few studies have been performed regarding the immunological analysis of the tumor microenvironment (TME) in chromatin remodeling complex gene-mutated tumors. In the present study, we identified cancer patients harboring various mammalian SWI/SNF complex mutations and investigated the immunological features in those mutated cancers. Patients and Methods: Cancer patients harboring any type of chromatin remodeling complex gene mutation were selected and clinicopathological features were compared between chromatin remodeling complex gene expression-low and expression-high groups. Specifically, expression levels of immune response-associated genes and cancer-associated genes were compared between the SMARCA4 expression-low and expression-high groups using volcano plot analysis. Results: Among cancers harboring PBRM1, SAMRACA4 and ARID2 gene mutations, T-cell marker and mature B-cell marker genes were up-regulated in the tumor. Specifically, T-cell effector genes (CD8B, CD40LG), central memory marker genes (CD27, CCR7) and mature B-cell marker genes (CD20, CD38, CD79 and IRF4) were up-regulated, and cancer-associated genes including MYB, MYC and AURKB genes were down-regulated in the SMARCA4 expression-low group. Remarkably, heatmap of gene expression and immunohistochemistry (IHC) data demonstrated that the tertiary lymphoid structure (TLS) gene signature of mature B cells was up-regulated in SMACA4 gene-mutated stomach cancers. Conclusion: These results suggest that immune tumor microenvironment status, such as mature B cell recruitment featuring the TLS gene signature and immune activation mediated by cancer signal downregulation, might contribute to the classification of SMARCA4 gene-mutated tumors as immune checkpoint blockade therapy-sensitive target tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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