Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1078228 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28012800_1.fastq.gz | Fastqsanger.gz | |||
| SRR28012800_2.fastq.gz | Fastqsanger.gz | |||
| SRR28012900_1.fastq.gz | Fastqsanger.gz | |||
| SRR28012900_2.fastq.gz | Fastqsanger.gz | |||
| SRR28012801_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 282 |
Similar Datasets
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
2024-03-11 | GSE256091 | GEO
Project description:Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations [MethylationEPIC]
| PRJNA1078231 | ENA
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.
2009-07-29 | GSE14936 | GEO
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. Twenty-eight pairs of lung cancer tissues and corresponding noncancerous lung tissues were obtained from never-smokers who had undergone surgical resection from 2000 to 2004 at the University of Maryland Medical Center (n=15), Mayo Clinic (n=7) in United States and Hamamatsu University School of Medicine (n=6) in Japan.
2010-05-15 | E-GEOD-14936 | biostudies-arrayexpress
Project description:Patients with lung adenocarcinoma who have never smoked (NSLA) and lack key driver mutations, such as those in the EGFR and ALK genes, face limited options for targeted therapies. They also tend to have poorer outcomes with immune checkpoint inhibitors than lung cancer patients who have a history of smoking. The proteogenomic profile of nonsmoking lung adenocarcinoma patients without these oncogenic driver mutations is poorly understood, which complicates the precise molecular classification of these cancers and highlights a significant area of unmet clinical need. This study analyzed the genome, transcriptome, and LC‒MS/MS-TMT-driven proteome data of tumors obtained from 99 Korean never-smoker lung adenocarcinoma patients. NSLA tumors without EGFR or ALK driver oncogenes were classified into four proteogenomic subgroups: proliferation, angiogenesis, immune, and metabolism subgroups. These 4 molecular subgroups were strongly associated with distinct clinical outcomes. The proliferation and angiogenesis subtypes were associated with a poorer prognosis, while the immune subtype was associated with the most favorable outcome, which was validated in an external lung cancer dataset. Genomic-wide impacts were analyzed, and significant correlations were found between copy number alterations and both the transcriptome and proteome for several genes, with enrichment in the ERBB, neurotrophin, insulin, and MAPK signaling pathways. Proteogenomic analyses suggested several targetable genes and proteins, including CDKs and ATR, as potential therapeutic targets in the proliferation subgroup. Upregulated cytokines, such as CCL5 and CXCL13, in the immune subgroup may serve as potential targets for combination immunotherapy. Our comprehensive proteogenomic analysis revealed the molecular subtypes of EGFR- and ALK-wild-type NSLA with significant unmet clinical needs.
| S-EPMC11446976 | biostudies-literature
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.
2024-03-12 | PXD033360 | Pride
Project description:Chronic obstructive pulmonary disease (COPD) is a progressive disease that obstructs the airflow from the lungs, and tobacco smoking is the major cause of COPD. Here, we applied single-cell RNA sequencing to analyze COPD pathogenesis in COPD patients, non-COPD smokers and never-smokers and investigated the disease progression at single-cell resolution. By single-cell transcriptome analysis, we identified a novel subpopulation of Alveolar Type 2 epithelial cells that emerged in smokers, such as COPD patients, and specifically expressed a series of chemokines and PD-L1. Since the number of cells in the basal cell clusters increased in only the COPD lungs but not in the non-COPD smoker or never-smoker lungs, we also tried to clarify the difference in phenotype between COPD and other basal cells with single-cell RNA-seq. However, due to the small number of cells in each, no clear difference could be found. To further investigate the functional properties of basal cells in COPD, we isolated small airway epithelial cells from surgical samples of COPD or never-smoker lungs and expanded the cells in vitro.Total RNA was extracted from early passaged cells , and bulk RNA-seq was performed to characterize these cells in detail. Finally, we found that the COPD basal cells retained the inflammatory response and basal/stem-related signals, even after a few passages in culture, and it might cause basal cell expansion in vivo.
2021-06-10 | GSE162154 | GEO
Project description:Epigenetic alterations are widespread in cancer and can complement genetic alterations to influence cancer progression and treatment. To better understand the potential contribution of DNA methylation alterations to tumor phenotype in non-small cell lung cancer (NSCLC) in both smoker and never-smoker patients, we performed a comprehensive, genome-wide profiling of DNA methylation in 17 primary non-small cell lung cancer and 10 matched normal lung samples using the complementary methylation assays MeDIP-seq and MRE-seq. Compared to patient-matched non-malignant lung tissue, we report recurrent methylation changes of several gene promoters, many previously implicated in cancer, including FAM83A and SEPT9 (hypomethylation), and PCDH7, NKX2-1, and SOX17 (hypermethylation). Although smoker and never-smoker patients shared many methylation changes, several were specific and recurrent within a particular smoking status. In particular, never-smokers displayed a greater proportion of hypoDMRs and exhibited a greater number of recurrently hypomethylated promoters, including the promoter of the oncogene ASPSCR1, and others previously linked to cancer, including TOP2A, DPP9, and USP39. Methylation changes outside of promoters were also widespread and often recurrent, particularly the loss of methylation over repetitive elements, highly enriched for ERV1 subfamilies. Recurrent hypoDMRs were also enriched for several transcription factor (TF) binding motifs, often for genes involved in signaling and cell proliferation, including 71% encoding a binding site of NKX2-1, which was found to be significantly upregulated in TCGA LUAD samples. Furthermore, the overwhelming majority of DMRs identified in this study were found to reside in an active chromatin state in at least one tissue profiled using the Roadmap Epigenome data, suggesting that methylation changes may contribute to altered regulatory programs through the adaptation of cell type-specific expression programs.
2023-09-16 | GSE210957 | GEO
Project description:ALK and ROS1 fusions defines subsets of lung adenocarcinoma. Although ALK/ROS1 inhibitors improved therapeutic outcome of patients harboring those oncogenic fusions, complete responses were rare, and resistance eventually develops from the residual tumor. To under the mechanisms contributing to residual tumor formation, we performed phosphoproteomics to explore the signaling adaption shortly after ALK/ROS1 inhibition. We found the phosphorylation of Mig6, a potent inhibitor for EGFR, was decreased following ALK/ROS1 inhibition, impairing Mig6 binding and inhibition on EGFR. Furthermore, Mig6 mRNA and protein levels were decreased rapidly by ALK/ROS1 inhibitors, potentiating EGFR activity to support cell survival. We also uncovered a novel mechanism mediated by Mig6 to regulate EGFR activity without impacting EGFR phosphorylation, but rather altering signaling adaptor SHC1 binding to EGFR. Mig6 expression was also lost following long-term exposure to ALK/ROS1 inhibitors to support EGFR-mediated acquired resistance. Finally, a Mig6 EGFR-binding domain truncation mutation was identified in a patient-derived ROS1 cell line, rendering its resistance to ROS1 inhibitors but sensitivity to HER family inhibitors. Our work established a rationale to evaluate combinations of ALK/ROS1 and EGFR inhibitors to limit residual tumor formation, therefore preventing or delaying subsequent resistance emergence.
2023-09-12 | PXD036771 | Pride