Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations [MethylationEPIC]
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ABSTRACT:
PROVIDER: PRJNA1078231 | ENA |
REPOSITORIES: ENA
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Project description:Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, and is even more in women. EGFR mutations and ALK fusions are major alterations observed in NSLA. We have focused on NSLA without EGFR and ALK alteration (NENA) rather than NSLA with EGFR and ALK (EA). First, we selected 141 NSLA tissues, and performed proteogenomic analyses including the whole-genome sequencing (WGS), transcriptome, methylation EPIC array, total proteome and phosphoproteome. We then excluded 40 patients with EA and 7 patients with NENA microsatellite instability. Genome analysis revealed that TP53 (25%), KRAS (22%), ROS1 fusion (14%), and SETD2 (11%) were the most frequently mutated genes in NENA patients. Proteogenomic impact analysis revealed that STK11 and ERBB2 somatic mutations had broader effects on cancer-associated genes in NENA. Through DNA copy-number alteration analysis, we identified 22 prognostic proteins, influencing transcriptomic and proteomic changes. Gene set enrichment analysis revealed that the estrogen signaling emerged as the key pathway activated in NENA. A lot of proteogenomic evidence supported the increased estrogen signaling, such as copy-number deletions in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14. Finally, saracatinib, an Src inhibitor, was suggested as a potential drug for targeting activated estrogen signaling in NENA, and was experimentally validated in vitro using cell line model. In this study, we enhanced our understanding of the etiology of NENA NSLA through the proteogenomic landscape, based on which we proposed saracatinib as an effective drug
2024-03-11 | GSE256092 | GEO
Project description:Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, and is even more in women. EGFR mutations and ALK fusions are major alterations observed in NSLA. We have focused on NSLA without EGFR and ALK alteration (NENA) rather than NSLA with EGFR and ALK (EA). First, we selected 141 NSLA tissues, and performed proteogenomic analyses including the whole-genome sequencing (WGS), transcriptome, methylation EPIC array, total proteome and phosphoproteome. We then excluded 40 patients with EA and 7 patients with NENA microsatellite instability. Genome analysis revealed that TP53 (25%), KRAS (22%), ROS1 fusion (14%), and SETD2 (11%) were the most frequently mutated genes in NENA patients. Proteogenomic impact analysis revealed that STK11 and ERBB2 somatic mutations had broader effects on cancer-associated genes in NENA. Through DNA copy-number alteration analysis, we identified 22 prognostic proteins, influencing transcriptomic and proteomic changes. Gene set enrichment analysis revealed that the estrogen signaling emerged as the key pathway activated in NENA. A lot of proteogenomic evidence supported the increased estrogen signaling, such as copy-number deletions in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14. Finally, saracatinib, an Src inhibitor, was suggested as a potential drug for targeting activated estrogen signaling in NENA, and was experimentally validated in vitro using cell line model. In this study, we enhanced our understanding of the etiology of NENA NSLA through the proteogenomic landscape, based on which we proposed saracatinib as an effective drug
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Project description:Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations [RNA-seq]
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Project description:Approximately 15% of lung cancer cases are not associated with smoking and show molecular and clinical characteristics distinct from those in smokers. Epidermal growth factor receptor (EGFR) gene mutations, which are correlated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), are more frequent in never-smoker lung cancers. In this study, microRNA (miRNA) expression profiling of 28 never-smoker lung cancer cases identified aberrantly expressed miRNAs, which were much fewer than in lung cancers of smokers and included miRNAs previously identified (e.g., upregulated miR-21) and unidentified (e.g., downregulated miR-138) in those smoker cases. The changes in expression of some of these miRNAs were more remarkable in cases with EGFR mutations than in those without: the most upregulated miRNA, miR-21, was more abundant in cancers with EGFR mutation. A significant correlation between phosphorylated-EGFR (p-EGFR) and miR-21 levels in lung carcinoma cell lines and the suppression of miR-21 by an EGFR-TKI, AG1478, suggested that the EGFR signaling pathway positively regulated miR-21 expression. In a never-smoker-derived lung adenocarcinoma cell line H3255 with mutant EGFR and high levels of p-EGFR and miR-21, antisense inhibition of miR-21 enhanced AG1478-induced apoptosis. In a never-smoker-derived adenocarcinoma cell line H441 with wild-type EGFR, the antisense miR-21 not only showed the additive effect with AG1478 but also induced apoptosis by itself. These results suggest that aberrantly increased expression of miR-21, which is further enhanced by the activated EGFR signaling pathway, plays a critical role in lung carcinogenesis in never-smokers and is a potential therapeutic target in both EGFR mutant and wild-type cases.
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Project description:Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations and even more in women. Since epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions are major alterations found in NSLA, studies have focused on NSLA with EGFR and ALK alteration (EA), but not for NSLA without EGFR and ALK alteration (NENA). To reveal the proteogenomic landscape of NENA, we selected 101 NSLA tissues without EGFR and ALK by targeted sequencing of 1597 FFPE samples, and performed multiomics analyses including whole genome, transcriptome, methylation EPIC array, total proteome, and phosphoproteome. Genome analysis revealed that TP53 (25%), KRAS (22%), ROS1 fusion (13%), SETD2 (11%), and ERRB2 (9%) were the most frequently mutated genes in NENA. Proteogenomic impact analysis found that STK11 and ERBB2 somatic mutations had more profound effects on cancer-associated genes in NENA. From DNA copy number alteration analysis, we identified 22 prognostic proteins whose expression was controlled through transcriptome from copy number alterations Intriguingly, from gene set enrichment analysis, estrogen signaling emerged as the key pathway activated in NENA compared with EA. Evidence from multiomics analysis including copy number gains in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14, also supported the increased estrogen signaling. Finally, the saracatinib, an Src inhibitor, was suggested as a potential drug for targeting activated estrogen signaling in NENA. Taken together, the proteogenomic landscape for NENA from this study will enhance our understanding of the etiology of NSLA.
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