Dataset Information

Clinical Prognostic Factors and Integrated Multi-Omics Studies Identify Potential Novel Therapeutic Targets for Pediatric Desmoid Tumor.

ABSTRACT:

Background

Desmoid tumor (DT), also known as desmoid-type fibromatosis (DTF) or aggressive fibromatosis (AF) is a rare mesenchymal tumor affecting both children and adults. It is non-metastasis but infiltrative, growing with a high recurrence rate to even cause serious health problems. This study investigates the biology of desmoid tumors through integrated multi-omics studies.

Methods

We systematically investigated the clinical data of 98 extra-abdominal cases in our pediatric institute and identified some critical clinical prognostic factors. Moreover, our integrated multi-omics studies (Whole Exome Sequencing, RNA sequencing, and untargeted metabolomics profiling) in the paired PDT tumor/matched normal tissues identified more novel mutations, and potential prognostic markers and therapeutic targets for PDTs.

Results

The top mutation genes, such as CTNNB1 (p.T41A and p.S45F) and MUC4 (p.T3775T, p.S3450S, etc.), were observed with a mutation in more than 40% of PDT patients. We also identified a panel of genes that are classed as the FDA-approved drug targets or Wnt/β-catenin signaling pathway-related genes. The integrated analysis identified pathways and key genes/metabolites that may be important for developing potential treatment of PDTs. We also successfully established six primary PDT cell lines for future studies.

Conclusions

These studies may promote the development of novel drugs and therapeutic strategies for PDTs.

SUBMITTER: Ning B

PROVIDER: S-EPMC9768966 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Clinical Prognostic Factors and Integrated Multi-Omics Studies Identify Potential Novel Therapeutic Targets for Pediatric Desmoid Tumor.

Ning Bo B Huang Peng P Zhu Lining L Ma Zhijie Z Chen Xiaoli X Xu Haojun H Ma Ruixue R Yao Chengyun C Zheng Pengfei P Xia Tian T Xia Hongping H

Biological procedures online 20221220 1

<h4>Background</h4>Desmoid tumor (DT), also known as desmoid-type fibromatosis (DTF) or aggressive fibromatosis (AF) is a rare mesenchymal tumor affecting both children and adults. It is non-metastasis but infiltrative, growing with a high recurrence rate to even cause serious health problems. This study investigates the biology of desmoid tumors through integrated multi-omics studies.<h4>Methods</h4>We systematically investigated the clinical data of 98 extra-abdominal cases in our pediatric in ...[more]

PMID: 36539683

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Project description:BackgroundTherapeutic targets supported by genetic evidence from genome-wide association studies (GWAS) show higher probability of success in clinical trials. GWAS is a powerful approach to identify links between genetic variants and phenotypic variation; however, identifying the genes driving associations identified in GWAS remains challenging. Integration of molecular quantitative trait loci (molQTL) such as expression QTL (eQTL) using mendelian randomization (MR) and colocalization analyses can help with the identification of causal genes. Careful interpretation remains warranted because eQTL can affect the expression of multiple genes within the same locus.MethodsWe used a combination of genomic features that include variant annotation, activity-by-contact maps, MR, and colocalization with molQTL to prioritize causal genes across 4,611 disease GWAS and meta-analyses from biobank studies, namely FinnGen, Estonian Biobank and UK Biobank.ResultsGenes identified using this approach are enriched for gold standard causal genes and capture known biological links between disease genetics and biology. In addition, we find that eQTL colocalizing with GWAS are statistically enriched for corresponding disease-relevant tissues. We show that predicted directionality from MR is generally consistent with matched drug mechanism of actions (> 85% for approved drugs). Compared to the nearest gene mapping method, genes supported by multi-omics evidences displayed higher enrichment in approved therapeutic targets (risk ratio 1.75 vs. 2.58 for genes with the highest level of support). Finally, using this approach, we detected anassociation between the IL6 receptor signal transduction gene IL6ST and polymyalgia rheumatica, an indication for which sarilumab, a monoclonal antibody against IL-6, has been recently approved.ConclusionsCombining variant annotation, activity-by-contact maps, and molQTL increases performance to identify causal genes, while informing on directionality which can be translated to successful target identification and drug development.

Project description:ObjectiveTo identify potential therapeutic targets and evaluate the safety profiles for Idiopathic Pulmonary Fibrosis (IPF) using a comprehensive multi-omics approach.MethodWe integrated genomic and transcriptomic data to identify therapeutic targets for IPF. First, we conducted a transcriptome-wide association study (TWAS) using the Omnibus Transcriptome Test using Expression Reference Summary data (OTTERS) framework, combining plasma expression quantitative trait loci (eQTL) data with IPF Genome-Wide Association Studies (GWAS) summary statistics from the Global Biobank (discovery) and Finngen (duplication). We then applied Mendelian randomization (MR) to explore causal relationships. RNA-seq co-expression analysis (bulk, single-cell and spatial transcriptomics) was used to identify critical genes, followed by molecular docking to evaluate their druggability. Finally, phenome-wide MR (PheW-MR) using GWAS data from 679 diseases in the UK Biobank assessed the potential adverse effects of the identified genes.ResultWe identified 696 genes associated with IPF in the discovery dataset and 986 genes in the duplication dataset, with 126 overlapping genes through TWAS. MR analysis revealed 29 causal genes in the discovery dataset, with 13 linked to increased and 16 to decreased IPF risk. Summary data-based MR (SMR) confirmed six essential genes: ANO9, BRCA1, CCDC200, EZH1, FAM13A, and SFR1. Bulk RNA-seq showed FAM13A upregulation and SFR1 and EZH1 downregulation in IPF. Single-cell RNA-seq revealed gene expression changes across cell types. Molecular docking identified binding solid affinities for essential genes with respiratory drugs, and PheW-MR highlighted potential side effects.ConclusionWe identified six key genes-ANO9, BRCA1, CCDC200, EZH1, FAM13A, and SFR1-as potential drug targets for IPF. Molecular docking revealed strong drug affinities, while PheW-MR analysis highlighted therapeutic potential and associated risks. These findings offer new insights for IPF treatment and further investigation of potential side effects.

Dataset Information

Clinical Prognostic Factors and Integrated Multi-Omics Studies Identify Potential Novel Therapeutic Targets for Pediatric Desmoid Tumor.

Background

Methods

Results

Conclusions

Publications

Clinical Prognostic Factors and Integrated Multi-Omics Studies Identify Potential Novel Therapeutic Targets for Pediatric Desmoid Tumor.

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