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Systemic analyses of expression patterns and clinical features for GIMAPs family members in lung adenocarcinoma.

ABSTRACT: GTPase of immunity-associated proteins (GIMAPs) are frequently prescribed as important components of immune regulation complexes, which were known to play key roles in lung adenocarcinoma. However, little is known about the function of distinct GIMAPs in lung adenocarcinoma. To address this issue, this study investigated the biological function and pathway of GIMAPs in lung adenocarcinoma using multiple public databases. Absent expression of GIMAPs was found in lung adenocarcinoma at mRNA and protein levels. While a purity-corrected value uncovered that all GIMAPs were positively associated with the immune infiltration of lung adenocarcinoma. Furthermore, the expressions of GIMAPs were considered to be negatively associated with clinical cancer stages, patient's gender and pathological tumor grades in patients with lung adenocarcinoma. Besides, higher mRNA expression of GIMAPs was significantly associated with longer overall survival of patients with lung adenocarcinoma. Taken together, these results may enable GIMAPs family members as diagnostic and survival biomarker candidates or even potential therapeutic targets for patients with lung adenocarcinoma.

SUBMITTER: Deng S

PROVIDER: S-EPMC7655191 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Systemic analyses of expression patterns and clinical features for GIMAPs family members in lung adenocarcinoma.

Deng Sisi S Zhang Zhi Z Lu Xiaoli X Zhou Qi Q Xia Shilin S Li Mi M

Aging 20201028 20

GTPase of immunity-associated proteins (GIMAPs) are frequently prescribed as important components of immune regulation complexes, which were known to play key roles in lung adenocarcinoma. However, little is known about the function of distinct GIMAPs in lung adenocarcinoma. To address this issue, this study investigated the biological function and pathway of GIMAPs in lung adenocarcinoma using multiple public databases. Absent expression of GIMAPs was found in lung adenocarcinoma at mRNA and pr ...[more]

PMID: 33115964

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Project description:AbstractLung adenocarcinoma (LUAD) is a lethal malignancy worldwide and a major public health concern. We explored the potential clinical significance for LUAD of ATP-binding cassette (ABC), sub-family C, consisting of ABCC1-6, 8-12, and cystic fibrosis transmembrane conductance regulator (CFTR).Five hundred LUAD patients from The Cancer Genome Atlas database were used for analysis, including differential expression and diagnostic and prognostic significance. Oncomine and MERAV databases were used to validate differential expression and diagnostic significance. A risk score model was constructed using prognosis-related ABCC members. Prognosis-related genes were further explored to correlate their expression with tumor stage progression. Interaction networks, including biological processes and metabolic pathways, were constructed using Cytoscape software and STRING website.ABCC1-3 consistently showed high expression in tumor tissues (all P ≤ 0.05). Most datasets indicated that ABCC5, 10, and 11 were highly expressed in tumor tissues whereas ABCC6, 9, and CFTR were highly expressed in nontumor tissues (all P ≤ 0.05). Diagnostic significance of ABCC3 and ABCC5 was consistently assessed and validated in three datasets (all area under the curve > 0.700) whereas ABCC6, 8, 10, 11, and CFTR were assessed in The Cancer Genome Atlas dataset and validated in one dataset (all area under the curve > 0.700). Prognostic analysis indicated that ABCC2, 6, and 8 mRNA expression was associated with survival of LUAD (all adjusted P ≤ .037). The risk score model constructed using ABCC2, 6, and 8 suggested prognostic significance for survival predictions. ABCC2 expression was associated with tumor stage, whereas ABCC6 and 8 were not. Interaction networks indicated that they were involved in establishment of localization, ion transport, plasma membrane, apical plasma membrane, adenylyl nucleotide binding, ABC transporters, ABC transporter disorders, ABC-family-protein-mediated transport, and bile secretion.Differentially expressed ABCC2 and ABCC5 might be diagnostic whereas ABCC2, 6, and 8 may be prognostic biomarkers for LUAD, possibly through ABC-family-mediated transporter disorders.

Project description:BackgroundLung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression.Methods and findingsWe performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2) (mutated in 9 [8.9%] samples) and ZKSCAN1 (mutated in 6 [5.9%] samples), and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0078), suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p < 2.5×10-50). The total number of somatic mutations (p = 0.0039) and the fraction of transitions (p = 5.5×10-4) were associated with increased risk of distant metastasis. Our study's limitations include a small number of LUAD patients for subgroup analyses and a single-sample design for investigation of subclonality.ConclusionsThese data provide a genomic characterization of LUAD pathogenesis and progression. The distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures, and may serve as a foundation for more effective treatments for this lethal disease. LUAD's high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes.

Dataset Information

Systemic analyses of expression patterns and clinical features for GIMAPs family members in lung adenocarcinoma.

Publications

Systemic analyses of expression patterns and clinical features for GIMAPs family members in lung adenocarcinoma.

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