Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas

Abstract Objectives To explore the clinical features, molecular characteristics, and immune landscape of lung adenocarcinoma patients with KEAP1/NFE2L2/CUL3 mutations. Methods The multi‐omics data from the GDC‐TCGA LUAD project of The Cancer Genome Atlas (TCGA) database were downloaded from the Xena...

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Autores principales:	Xing Jin, Yuansheng Zheng, Zhencong Chen, Fei Wang, Guoshu Bi, Ming Li, Jiaqi Liang, Qihai Sui, Yunyi Bian, Zhengyang Hu, Yulei Qiao, Songtao Xu
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	cullin 3 (CUL3) kelch‐like ECH‐associated protein 1 (KEAP1) lung adenocarcinoma (LUAD) mutation nuclear factor erythroid 2‐like 2 (NFE2L2) Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/9bf3bd92b7a34467a1b86e2ceee31faf
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spelling	oai:doaj.org-article:9bf3bd92b7a34467a1b86e2ceee31faf2021-12-01T04:49:16ZIntegrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas2045-763410.1002/cam4.4338https://doaj.org/article/9bf3bd92b7a34467a1b86e2ceee31faf2021-12-01T00:00:00Zhttps://doi.org/10.1002/cam4.4338https://doaj.org/toc/2045-7634Abstract Objectives To explore the clinical features, molecular characteristics, and immune landscape of lung adenocarcinoma patients with KEAP1/NFE2L2/CUL3 mutations. Methods The multi‐omics data from the GDC‐TCGA LUAD project of The Cancer Genome Atlas (TCGA) database were downloaded from the Xena browser. The estimate of the immune infiltration was implemented by using the GSVA analysis and CIBERSORT. The status of KEAP1/NFE2L2/CUL3 mutation in 50 LUAD samples of our department was detected by using Sanger sequencing, following the relative expression level of differentially expressed genes (DEGs), miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs) was validated by IHC and real‐time quantitative polymerase chain reaction (RT‐qPCR). Results The Kaplan–Meier and multivariable Cox regression analyses demonstrated that KEAP1/NFE2L2/CUL3 mutations had independent prognostic value for OS and PFS in LUAD patients. The differential analysis detected 207 upregulated genes (like GSR/UGT1A6) and 447 downregulated genes (such as PIGR). GO, KEGG, and GSEA analyses demonstrated that DEGs were enriched in glutamate metabolism and the immune response. The constructed ceRNA network shows the linkage of differential lncRNAs and mRNAs. Three hundred and nine somatic mutations were detected, alterations in immune infiltration DNA methylations and stemness scores were also founded between the two groups. Eight mutated LUAD patients were detected by Sanger DNA sequencing in 50 surgical patients. GSR and UGT1A6 were validated to express higher in the Mut group, whereas the expression of PIGR was restrained. Furthermore, the IHC staining conducted on paraffin‐embedded tissue emphasizes the consistency of our result. Conclusion This research implemented the comprehensive analysis of KEAP1/NFE2L2/CUL3 somatic mutations in the LUAD patients. Compared with the wild type of LUAD patients, the Mut group shows a large difference in clinical features, RNA sequence, DNA methylation, and immune infiltrations, indicating complex mechanism oncogenesis and also reveals potential therapeutic targets.Xing JinYuansheng ZhengZhencong ChenFei WangGuoshu BiMing LiJiaqi LiangQihai SuiYunyi BianZhengyang HuYulei QiaoSongtao XuWileyarticlecullin 3 (CUL3)kelch‐like ECH‐associated protein 1 (KEAP1)lung adenocarcinoma (LUAD)mutationnuclear factor erythroid 2‐like 2 (NFE2L2)Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancer Medicine, Vol 10, Iss 23, Pp 8673-8692 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cullin 3 (CUL3) kelch‐like ECH‐associated protein 1 (KEAP1) lung adenocarcinoma (LUAD) mutation nuclear factor erythroid 2‐like 2 (NFE2L2) Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	cullin 3 (CUL3) kelch‐like ECH‐associated protein 1 (KEAP1) lung adenocarcinoma (LUAD) mutation nuclear factor erythroid 2‐like 2 (NFE2L2) Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Xing Jin Yuansheng Zheng Zhencong Chen Fei Wang Guoshu Bi Ming Li Jiaqi Liang Qihai Sui Yunyi Bian Zhengyang Hu Yulei Qiao Songtao Xu Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas
description	Abstract Objectives To explore the clinical features, molecular characteristics, and immune landscape of lung adenocarcinoma patients with KEAP1/NFE2L2/CUL3 mutations. Methods The multi‐omics data from the GDC‐TCGA LUAD project of The Cancer Genome Atlas (TCGA) database were downloaded from the Xena browser. The estimate of the immune infiltration was implemented by using the GSVA analysis and CIBERSORT. The status of KEAP1/NFE2L2/CUL3 mutation in 50 LUAD samples of our department was detected by using Sanger sequencing, following the relative expression level of differentially expressed genes (DEGs), miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs) was validated by IHC and real‐time quantitative polymerase chain reaction (RT‐qPCR). Results The Kaplan–Meier and multivariable Cox regression analyses demonstrated that KEAP1/NFE2L2/CUL3 mutations had independent prognostic value for OS and PFS in LUAD patients. The differential analysis detected 207 upregulated genes (like GSR/UGT1A6) and 447 downregulated genes (such as PIGR). GO, KEGG, and GSEA analyses demonstrated that DEGs were enriched in glutamate metabolism and the immune response. The constructed ceRNA network shows the linkage of differential lncRNAs and mRNAs. Three hundred and nine somatic mutations were detected, alterations in immune infiltration DNA methylations and stemness scores were also founded between the two groups. Eight mutated LUAD patients were detected by Sanger DNA sequencing in 50 surgical patients. GSR and UGT1A6 were validated to express higher in the Mut group, whereas the expression of PIGR was restrained. Furthermore, the IHC staining conducted on paraffin‐embedded tissue emphasizes the consistency of our result. Conclusion This research implemented the comprehensive analysis of KEAP1/NFE2L2/CUL3 somatic mutations in the LUAD patients. Compared with the wild type of LUAD patients, the Mut group shows a large difference in clinical features, RNA sequence, DNA methylation, and immune infiltrations, indicating complex mechanism oncogenesis and also reveals potential therapeutic targets.
format	article
author	Xing Jin Yuansheng Zheng Zhencong Chen Fei Wang Guoshu Bi Ming Li Jiaqi Liang Qihai Sui Yunyi Bian Zhengyang Hu Yulei Qiao Songtao Xu
author_facet	Xing Jin Yuansheng Zheng Zhencong Chen Fei Wang Guoshu Bi Ming Li Jiaqi Liang Qihai Sui Yunyi Bian Zhengyang Hu Yulei Qiao Songtao Xu
author_sort	Xing Jin
title	Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas
title_short	Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas
title_full	Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas
title_fullStr	Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas
title_full_unstemmed	Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas
title_sort	integrated analysis of patients with keap1/nfe2l2/cul3 mutations in lung adenocarcinomas
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/9bf3bd92b7a34467a1b86e2ceee31faf
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Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas

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