Pathway-based subnetworks enable cross-disease biomarker discovery

Haider, Syed; Yao, Cindy Q.; Sabine, Victoria; Grzadkowski, Michal R.; Stimper, Vincent; Starmans, Maud H.W.; Wang, Jianxin; Nguyen, Francis; Moon, Nathalie C.; Lin, Xihui; Drake, Camilla; Crozier, Cheryl; Brookes, Cassandra; Velde, Cornelis J.H. van de; Hasenburg, Annette; Kieback, Dirk G.; Markopoulos, Christos; Dirix, Luc; Seynaeve, Caroline; Rea, Daniel; Kasprzyk, Arek; Lambin, Philippe; Lió, Píetro; Bartlett, John M.S.; Boutros, Paul C.

doi:10.1038/s41467-018-07021-3

Cited by 35 publications

(22 citation statements)

References 62 publications

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“…These results that motivate further studies into TC–TAC interactions and the contribution of TAC transcriptome changes to cancer development and progression. There are many existing datasets in which the approach demonstrated here could be used to explore TAC biology, particularly in a pathway context 39 . Overall our results suggest that in silico derived TC and TAC mRNA abundance are an advantageous framework to explore the complex transcriptional network between tumours, their microenvironments and cancer aggression.…”

Section: Discussionmentioning

confidence: 99%

Landscape of transcriptomic interactions between breast cancer and its microenvironment

et al. 2019

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Solid tumours comprise mixtures of tumour cells (TCs) and tumour-adjacent cells (TACs), and the intricate interconnections between these diverse populations shape the tumour’s microenvironment. Despite this complexity, clinical genomic profiling is typically performed from bulk samples, without distinguishing TCs from TACs. To better understand TC–TAC interactions, we computationally distinguish their transcriptomes in 1780 primary breast tumours. We show that TC and TAC mRNA abundances are divergently associated with clinical phenotypes, including tumour subtypes and patient survival. These differences reflect distinct responses of TCs and TACs to specific somatic driver mutations, particularly TP53 . These data further elucidate how the molecular interplay between breast tumours and their microenvironment drives aggressive tumour phenotypes.

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Section: Discussionmentioning

confidence: 99%

Landscape of transcriptomic interactions between breast cancer and its microenvironment

et al. 2019

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“…inflammatory reaction to gluten) could in theory be accomplished by different genetic predispositions, which could also affect the expressions of different genes. Pathway information has been shown to be useful for predicting individual risk for disease 184,185 . Although a few solitary biomarkers could be advantageous in the diagnosis of CD, basing gene expression profiles on pathway information instead of single genes might also reveal disease heterogeneity between patients and add stability to a diagnostic method based on gene expressions.…”

Section: Discussionmentioning

confidence: 99%

Biomarkers of Inflammation and Intestinal Mucosa Pathology in Celiac Disease

Bragde

2019

Linköping University Medical Dissertations

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Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy triggered by gluten. The only currently available treatment is complying with a lifelong gluten-free diet, which should not be commenced before a CD diagnosis has been established by diagnostic test results (including histopathologic assessment of small intestinal biopsies and CD-specific antibody levels). This makes diagnostic swiftness and accuracy important. In cases with low CD-specific antibody levels and/or low-grade intestinal injuries the diagnosis can be difficult to establish. The main objective of this thesis was to complement and improve CD diagnostics by identifying and implementing new biomarkers, mainly based on gene expression, in small intestinal biopsies and blood. In paper I, genes were selected to reflect villous height, crypt elongation, immune response, and epithelial integrity. The results showed that a subset of those genes could discriminate active CD mucosa from mucosa without CD-related changes and grade the intestinal injury. In paper III, an unbiased investigation of gene expression in CD mucosa was performed using transcriptome analysis. Active CD and non-CD mucosa showed differential expression in a subset of genes, and some were differentially expressed in CD mucosa before histopathologic assessment could confirm intestinal alterations compatible with a CD diagnosis. Gene set analysis revealed that there are many biological processes affected in CD mucosa, including those associated with immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation. In parallel, gene expression was investigated in stabilised whole blood. Blood is a more accessible sampling material than intestinal biopsies, and stabilised blood is suitable for routine diagnostics since transcript levels are preserved at sampling. In paper II, expressions from a selection of genes were quantified in stabilised whole blood (RNA) and/or plasma (protein). Three genes with differential expression in CD were identified. Compared to the CD-specific autoantibodies against tissue transglutaminase (anti-TG2) alone, the addition of the information from the new potential markers resulted in a non-significant contribution to the diagnostic capacity of anti-TG2. An unbiased investigation using transcriptome analysis (paper IV) showed that gene level expression differences in stabilised whole blood were small between CD and non-CD. However, expression differences on a gene set level could potentially be used in CD diagnostics. CD-associated biological processes suggested UBD ubiquitin D ULN upper limit of normal ZFR zinc finger RNA binding protein Contents ix Contents Introduction .

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“…Thus, we excluded the highly overlapping pathways and then re-implemented our method. Specifically, according to the method of eliminating redundancy proposed by Haider et al (2018), we tested the overlap between each pair of pathways and eliminated the smaller one when a pair of pathways had a two-way overlap above 80% (if two pathways shared over 80% of their genes). In the end, we obtained 199 mRNA pathways and 102 microRNA pathways, which we called nonredundant KEGG (non-reKEGG) pathways.…”

Section: Robustness Analysis Of Priorcd Methodsmentioning

confidence: 99%

Prioritization of candidate cancer drugs based on a drug functional similarity network constructed by integrating pathway activities and drug activities

Zheng

Kong

et al. 2019

Molecular Oncology

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Due to the speed, efficiency, relative risk, and lower costs compared to traditional drug discovery, the prioritization of candidate drugs for repurposing against cancers of interest has attracted the attention of experts in recent years. Herein, we present a powerful computational approach, termed prioritization of candidate drugs (PriorCD), for the prioritization of candidate cancer drugs based on a global network propagation algorithm and a drug–drug functional similarity network constructed by integrating pathway activity profiles and drug activity profiles. This provides a new approach to drug repurposing by first considering the drug functional similarities at the pathway level. The performance of PriorCD in drug repurposing was evaluated by using drug datasets of breast cancer and ovarian cancer. Cross‐validation tests on the drugs approved for the treatment of these cancers indicated that our approach can achieve area under receiver‐operating characteristic curve (AUROC) values greater than 0.82. Furthermore, literature searches validated our results, and comparison with other classical gene‐based repurposing methods indicated that our pathway‐level PriorCD is comparatively more effective at prioritizing candidate drugs with similar therapeutic effects. We hope that our study will be of benefit to the field of drug discovery. In order to expand the usage of PriorCD, a freely available R‐based package, PriorCD, has been developed to prioritize candidate anticancer drugs for drug repurposing.

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Pathway-based subnetworks enable cross-disease biomarker discovery

Cited by 35 publications

References 62 publications

Landscape of transcriptomic interactions between breast cancer and its microenvironment

Landscape of transcriptomic interactions between breast cancer and its microenvironment

Biomarkers of Inflammation and Intestinal Mucosa Pathology in Celiac Disease

Prioritization of candidate cancer drugs based on a drug functional similarity network constructed by integrating pathway activities and drug activities

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