scholarly journals Mutation Enrichment and Transcriptomic Activation Signatures of 419 Molecular Pathways in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 271 ◽  
Author(s):  
Marianna A. Zolotovskaia ◽  
Victor S. Tkachev ◽  
Alexander P. Seryakov ◽  
Denis V. Kuzmin ◽  
Dmitry E. Kamashev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Gene Networks ◽  
The Other ◽  
Molecular Pathways ◽  
Dna Mutations ◽  
Whole Exome ◽  
Pathway Activation ◽  
Cancer Types ◽  
First Time

Carcinogenesis is linked with massive changes in regulation of gene networks. We used high throughput mutation and gene expression data to interrogate involvement of 278 signaling, 72 metabolic, 48 DNA repair and 47 cytoskeleton molecular pathways in cancer. Totally, we analyzed 4910 primary tumor samples with individual cancer RNA sequencing and whole exome sequencing profiles including ~1.3 million DNA mutations and representing thirteen cancer types. Gene expression in cancers was compared with the corresponding 655 normal tissue profiles. For the first time, we calculated mutation enrichment values and activation levels for these pathways. We found that pathway activation profiles were largely congruent among the different cancer types. However, we observed no correlation between mutation enrichment and expression changes both at the gene and at the pathway levels. Overall, positive median cancer-specific activation levels were seen in the DNA repair, versus similar slightly negative values in the other types of pathways. The DNA repair pathways also demonstrated the highest values of mutation enrichment. However, the signaling and cytoskeleton pathways had the biggest proportions of representatives among the outstandingly frequently mutated genes thus suggesting their initiator roles in carcinogenesis and the auxiliary/supporting roles for the other groups of molecular pathways.

Tumor mutation burden and PD-L1 expression in SDH/FH mutated solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1524-1524
Author(s):  
Leylah Drusbosky ◽  
Christopher Szeto ◽  
Sandeep K. Reddy ◽  
Maninderjit Ghotra ◽  
Amir A. Toor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Checkpoint ◽  
Tumor Tissue ◽  
Fumarate Hydratase ◽  
Tumor Mutation Burden ◽  
Whole Exome ◽  
Mutation Burden ◽  
Potential Therapeutic Role ◽  
Tumor Types ◽  
First Time

1524 Background: Succinate Dehydrogenases and Fumarate Hydratase (SDH/FH) deficient tumors are characterized by succinate/fumarate accumulation and resultant pesudohypoxia that drives malignant transformation. This state of pseudohypoxia leads to dysregulation of PD-1 receptor-ligand signaling. In this study, we explored tumor mutation burden (TMB), gene expression of PD-L1, and expression of other immune checkpoint- associated genes in a diverse cohort of human tumors harboring SDH A, B, C, D and FH mutations. Methods: Retrospective analysis was performed on whole exome sequencing (WES; ~150x coverage) and whole transcriptomic RNAseq (~200x106 reads per tumor) data from NantHealth to identify tumors harboring SDHx and/or FH mutations. WES was performed on tumor tissue and matched normal for each patient to assess TMB. TMB was measured by counting all somatic-specific non-synonymous exonic mutations, with > 200 mutations qualified as TMB-high. Immune checkpoint therapy-related gene expression was evaluated for PDL1, CTLA4 , IDO, LAG3, FOXP3, PDL2, TIGIT, TIM3 and OX40 . Results: Among tumor samples from 3377 patients analyzed, 42 patients were found to harbor potentially-pathogenic & pathogenic mutations in the SDHA, B, C, D and FH genes. The most common tumor types with SDH/FH mutations were lung (n = 7), breast (n = 6), and colon cancer (n = 6). Our analysis revealed that TMB was positively correlated with the presence of SDH/FH mutations (p < 0.001). High PD-L1 expression was also significantly correlated with the presence of SDH/FH mutation (p < 0.05), while CTLA4, IDO, LAG3, FOXP3, and OX40 expression was significantly higher in SDH/FH mutated samples (p < 0.05). Conclusions: We report for the first time an association between increased TMB and increased PD-L1 expression in a variety of SDH/FH mutated tumors. These key parameters, imply that a higher TMB may drive the evolutionary pressure to select clones with a PDL1 high phenotype. This observation supports a potential therapeutic role for inhibition of PD-1/PD-L1 pathway in these tumors.

scholarly journals Alteration to the SWI/SNF complex in human cancers

2011 ◽  
Vol 4 (2) ◽  
pp. 89
Author(s):  
Vanessa S. Gordon ◽  
Colin Rogers ◽  
David Reisman
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Cell Adhesion ◽  
Growth Control ◽  
Cellular Growth ◽  
Cancer Development ◽  
Catalytic Subunits ◽  
Cancer Types ◽  
Potential Impact ◽  
The Impact

The SWI/SNF complex is a key catalyst for gene expression and regulates a variety of pathways, many of which have anticancer roles. Its central roles in cellular growth control, DNA repair, differentiation, cell adhesion and development are often targeted, and inactivated, during cancer development and progression. In this review, we will discuss what is known about how SWI/SNF is inactivated, and describe the potential impact of abrogating this complex. BRG1 and BRM are the catalytic subunits which are essential for SWI/SNF function, and thus, it is not surprising that they are lost in a variety of cancer types. As neither gene is mutated when lost, the mechanism of suppression, as well as the impact of potential gene activity restoration, are reviewed.

scholarly journals Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation

2017 ◽  
Vol 29 (2) ◽  
pp. 423-433 ◽  
Author(s):  
Lorenzo Gallon ◽  
James M. Mathew ◽  
Sai Vineela Bontha ◽  
Catherine I. Dumur ◽  
Pranav Dalal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Rejection ◽  
B Cell ◽  
Gene Networks ◽  
Expression Profiles ◽  
Tolerance Induction ◽  
Cell Receptor ◽  
Molecular Pathways ◽  
Inflammatory Pathways ◽  
Integrative Analyses

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell– and B cell–mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways.

scholarly journals PhytoNet: Comparative co-expression network analyses across phytoplankton and land plants

2018 ◽  
Author(s):  
Camilla Ferrari ◽  
Sebastian Proost ◽  
Colin Ruprecht ◽  
Marek Mutwil
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Gene Networks ◽  
Photosynthetic Activity ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Land Plants ◽  
Expression Data ◽  
Network Analyses ◽  
Crucial Component

ABSTRACTPhytoplankton consists of autotrophic, photosynthesizing microorganisms that are a crucial component of freshwater and ocean ecosystems. However, despite being the major primary producers of organic compounds, accounting for half of the photosynthetic activity worldwide and serving as the entry point to the food chain, functions of most of the genes of the model phytoplankton organisms remain unknown. To remedy this, we have gathered publicly available expression data for one chlorophyte, one rhodophyte, one haptophyte, two heterokonts and four cyanobacteria and integrated it into our PlaNet (Plant Networks) database, which now allows mining gene expression profiles and identification of co-expressed genes of 19 species. We exemplify how the co-expressed gene networks can be used to reveal functionally related genes and how the comparative features of PhytoNet allow detection of conserved transcriptional programs between cyanobacteria, green algae, and land plants. Additionally, we illustrate how the database allows detection of duplicated transcriptional programs within an organism, as exemplified by two DNA repair programs within Chlamydomonas reinhardtii. PhytoNet is available from www.gene2function.de.

scholarly journals Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sarah H. Kim ◽  
Arnaud Da Cruz Paula ◽  
Thais Basili ◽  
Higinio Dopeso ◽  
Rui Bi ◽  
...  
Keyword(s):  
Stromal Tumor ◽  
Phenotypic Correlation ◽  
Rare Type ◽  
Shh Pathway ◽  
Whole Exome ◽  
Pathway Activation ◽  
Sclerosing Stromal Tumor ◽  
Cancer Types ◽  
Targeted Inhibition

AbstractSclerosing stromal tumor (SST) of the ovary is a rare type of sex cord-stromal tumor (SCST), whose genetic underpinning is currently unknown. Here, using whole-exome, targeted capture and RNA-sequencing, we report recurrent FHL2-GLI2 fusion genes in 65% (17/26) of SSTs and other GLI2 rearrangements in additional 15% (4/26) SSTs, none of which are detected in other types of SCSTs (n = 48) or common cancer types (n = 9,950). The FHL2-GLI2 fusions result in transcriptomic activation of the Sonic Hedgehog (SHH) pathway in SSTs. Expression of the FHL2-GLI2 fusion in vitro leads to the acquisition of phenotypic characteristics of SSTs, increased proliferation, migration and colony formation, and SHH pathway activation. Targeted inhibition of the SHH pathway results in reversal of these oncogenic properties, indicating its role in the pathogenesis of SSTs. Our results demonstrate that the FHL2-GLI2 fusion is likely the oncogenic driver of SSTs, defining a genotypic–phenotypic correlation in ovarian neoplasms.

71 Whole exome sequencing of individuals presenting extreme phenotypes of high and low-risk of developing tobacco-induced lung adenocarcinoma: relevance of immune and DNA-repair related pathways

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A77-A77
Author(s):  
Jose Perez-Gracia ◽  
Mapi Andueza ◽  
Ana Patiño-Garcia ◽  
Alfonso Gurpide
Keyword(s):  
Dna Repair ◽  
Lung Adenocarcinoma ◽  
Genetic Background ◽  
Statistical Significance ◽  
Tobacco Consumption ◽  
Pathway Database ◽  
Database Analysis ◽  
Whole Exome ◽  
Extreme Phenotypes ◽  
First Time

BackgroundIndividual susceptibility to carcinogens may depend on genetic background. We performed for the first-time Whole Exome Sequencing (WES) of germline DNA from individuals presenting phenotypes of extreme sensitivity and resistance to developing tobacco-induced lung adenocarcinoma, in order to characterize the genetic background associated with these relevant phenotypes.MethodsWe performed WES of germline DNA from heavy smokers (≥15 pack-years) who either developed lung adenocarcinoma at an early age (≤55 years, extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (≥72 years, extreme controls, n=50). We selected non-synonymous variants (missense and non-sense) located in the coding regions and consensus splice sites of the genes showing significantly different allelic frequencies between both cohorts. We validated our results in germline data from 52 additional extreme cases selected from TCGA using the same criteria (diagnosis of lung adenocarcinoma at ≤55 years, tobacco consumption ≥15 pack-years).ResultsThe mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.5 and 54.4 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 107 of these in 52 extreme cases selected from TCGA (mean age 49.3 years, mean tobacco consumption 37 pack-years). Nine validated variants, located in relevant cancer related genes, such as PARP4 (DNA repair), HLA-A (antigen presentation) or NQO1 (detoxification) among others, achieved statistical significance in the False Discovery Rate test (FDR) (table 1). The most significant validated variant (p=4.48 × 10-5) was located in the tumor-suppressor gene ALPK2. The Reactome Pathway Database analysis showed that the genes harboring the most significant validated variants were significantly related to antigen processing and presentation, interferon and cytokine signaling and immune regulation, also achieving statistical significance in the FDR test (table 2).Abstract 71 Table 1Most significant validated variants.Abstract 71 Table 2Reactome pathway database analysis of pathways related to the genes that harbor the validated variantsConclusionsWe describe for the first time genetic variants associated with extreme phenotypes of high and low-risk for the development of tobacco-induced lung adenocarcinoma, assessed with WES. The most significant validated variants were related with antigen presentation, immune regulation and DNA repair. Our results and our strategy warrant further development to characterize these clinically relevant phenotypes.Ethics ApprovalThe study was approved by the Investigational Review Board of Clinica Universidad de Navarra, approval number 021/2009.

scholarly journals 93 Computational biology and tissue-based approaches to inform indication selection for a novel AHR inhibitor

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A102-A102
Author(s):  
Marta Sanchez-Martin ◽  
Lei Wang ◽  
Jeffrey Ecsedy ◽  
Karen Mcgovern ◽  
Michelle Zhang
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Aryl Hydrocarbon Receptor ◽  
Protein Detection ◽  
Transcriptional Analysis ◽  
Tumor Type ◽  
Aryl Hydrocarbon ◽  
Pathway Activation ◽  
Cancer Types ◽  
Ahr Gene

BackgroundAryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor that regulates the activities of multiple innate and adaptive immune cell types. Multiple ligands such as kynurenine bind to AHR driving its nuclear translocation and transcriptional activation, leading to an immunosuppressive tumor microenvironment.1 2 AHR activation is implicated in tumor development in multiple cancer types. In addition, high levels of serum kynurenine are associated with resistance to checkpoint inhibitors.3 To overcome AHR-mediated immunosuppression in cancers, we developed a selective oral AHR inhibitor IK-175 and took a combined computational and tissue-based approach to select cancer indications for its clinical development.MethodsThe aim of this work is to identify tumor indications dependent on AHR signaling and design patient selection strategies based on a proprietary transcriptional signature, mRNA and protein detection assays to evaluate AHR pathway activation in tumors.ResultsGenomic profiling of solid and hematological cancers from TCGA and Project GENIE databases identified bladder and esophageal tumors among others, as frequently harboring AHR gene amplifications.A proprietary gene signature of AHR activation was developed integrating literature, pathway analysis, RNAseq and nanostring data from PBMC, T-cells and cell lines upon AHR inhibition. Transcriptional analysis of the TCGA data using this signature demonstrated bladder cancer has the highest expressions of AHR and AHR signature genes, suggesting increased pathway activity in bladder cancer relative to other cancer types. Increased AHR signature gene expression was associated with worse overall survival in the TCGA bladder cancer cohort. Furthermore, RNAscope analysis of a tissue microarray containing 10 different tumor types revealed bladder cancer had one of the highest AHR transcript expression in the tumor compartment.Finally, nuclear localization of AHR protein was assessed as an indicator of pathway activation through the development of a novel IHC method. Extensive TMA screening of AHR protein in 15 different indications demonstrated bladder cancer as the tumor type with the highest prevalence of AHR nuclear expression.ConclusionsIn summary, we demonstrated high prevalence of nuclear AHR protein expression, AHR gene amplification and target gene expression in bladder cancer, suggesting aberrant AHR activation may play an important role in the progression of this tumor type. This study provides rationale for therapeutic targeting of AHR in bladder cancer patients. Ikena is currently evaluating the anti-tumor activity of IK-175 as a single agent and in combination with nivolumab in bladder cancer in a Phase 1a/1b clinical study (NCT04200963).ReferencesQuintana FJ, Sherr DH. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev 2013 Aug 1;65(4):1148–61.Murray IA, Patterson AD, Perdew GH. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 2014 Dec;14(12):801–14.Li, Haoxin et al. ‘Metabolomic adaptations and correlates of survival to immune checkpoint blockade.’ Nature Communications 2019 Sep 25;10:1–4346.

scholarly journals Algorithmic Annotation of Functional Roles for Components of 3,044 Human Molecular Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Maxim Sorokin ◽  
Nicolas Borisov ◽  
Denis Kuzmin ◽  
Alexander Gudkov ◽  
Marianna Zolotovskaia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
High Throughput ◽  
Large Scale ◽  
Direct Calculation ◽  
Molecular Pathways ◽  
Expression Data ◽  
Functional Roles ◽  
Pathway Activation ◽  
Pathway Regulation

Current methods of high-throughput molecular and genomic analyses enabled to reconstruct thousands of human molecular pathways. Knowledge of molecular pathways structure and architecture taken along with the gene expression data can help interrogating the pathway activation levels (PALs) using different bioinformatic algorithms. In turn, the pathway activation profiles can characterize molecular processes, which are differentially regulated and give numeric characteristics of the extent of their activation or inhibition. However, different pathway nodes may have different functions toward overall pathway regulation, and calculation of PAL requires knowledge of molecular function of every node in the pathway in terms of its activator or inhibitory role. Thus, high-throughput annotation of functional roles of pathway nodes is required for the comprehensive analysis of the pathway activation profiles. We proposed an algorithm that identifies functional roles of the pathway components and applied it to annotate 3,044 human molecular pathways extracted from the Biocarta, Reactome, KEGG, Qiagen Pathway Central, NCI, and HumanCYC databases and including 9,022 gene products. The resulting knowledgebase can be applied for the direct calculation of the PALs and establishing large scale profiles of the signaling, metabolic, and DNA repair pathway regulation using high throughput gene expression data. We also provide a bioinformatic tool for PAL data calculations using the current pathway knowledgebase.

scholarly journals Loss of TGFβ signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types

2021 ◽  
Vol 13 (580) ◽  
pp. eabc4465
Author(s):  
Qi Liu ◽  
Luis Palomero ◽  
Jade Moore ◽  
Ines Guix ◽  
Roderic Espín ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
End Joining ◽  
Tgfβ Signaling ◽  
Damage Response ◽  
Gene Expression Signatures ◽  
Alternative End Joining ◽  
Cancer Types

Among the pleotropic roles of transforming growth factor–β (TGFβ) signaling in cancer, its impact on genomic stability is least understood. Inhibition of TGFβ signaling increases use of alternative end joining (alt-EJ), an error-prone DNA repair process that typically functions as a “backup” pathway if double-strand break repair by homologous recombination or nonhomologous end joining is compromised. However, the consequences of this functional relationship on therapeutic vulnerability in human cancer remain unknown. Here, we show that TGFβ broadly controls the DNA damage response and suppresses alt-EJ genes that are associated with genomic instability. Mechanistically based TGFβ and alt-EJ gene expression signatures were anticorrelated in glioblastoma, squamous cell lung cancer, and serous ovarian cancer. Consistent with error-prone repair, more of the genome was altered in tumors classified as low TGFβ and high alt-EJ, and the corresponding patients had better outcomes. Pan-cancer analysis of solid neoplasms revealed that alt-EJ genes were coordinately expressed and anticorrelated with TGFβ competency in 16 of 17 cancer types tested. Moreover, regardless of cancer type, tumors classified as low TGFβ and high alt-EJ were characterized by an insertion-deletion mutation signature containing short microhomologies and were more sensitive to genotoxic therapy. Collectively, experimental studies revealed that loss or inhibition of TGFβ signaling compromises the DNA damage response, resulting in ineffective repair by alt-EJ. Translation of this mechanistic relationship into gene expression signatures identified a robust anticorrelation that predicts response to genotoxic therapies, thereby expanding the potential therapeutic scope of TGFβ biology.

scholarly journals New Phosphorylation Sites of Rad51 by c-Met Modulates Presynaptic Filament Stability

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 413 ◽  
Author(s):  
Thomas Chabot ◽  
Alain Defontaine ◽  
Damien Marquis ◽  
Axelle Renodon-Corniere ◽  
Emmanuelle Courtois ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Tyrosine Kinases ◽  
Post Translational Modifications ◽  
Subunit Interface ◽  
Central Protein ◽  
Cancer Types ◽  
First Time

Genomic instability through deregulation of DNA repair pathways can initiate cancer and subsequently result in resistance to chemo and radiotherapy. Understanding these biological mechanisms is therefore essential to overcome cancer. RAD51 is the central protein of the Homologous Recombination (HR) DNA repair pathway, which leads to faithful DNA repair of DSBs. The recombinase activity of RAD51 requires nucleofilament formation and is regulated by post-translational modifications such as phosphorylation. In the last decade, studies have suggested the existence of a relationship between receptor tyrosine kinases (RTK) and Homologous Recombination DNA repair. Among these RTK the c-MET receptor is often overexpressed or constitutively activated in many cancer types and its inhibition induces the decrease of HR. In this study, we show for the first time that c-MET is able to phosphorylate the RAD51 protein. We demonstrate in vitro that c-MET phosphorylates four tyrosine residues localized mainly in the subunit-subunit interface of RAD51. Whereas these post-translational modifications do not affect the presynaptic filament formation, they strengthen its stability against the inhibitor effect of the BRC peptide obtained from BRCA2. Taken together, these results confirm the role of these modifications in the regulation of the BRCA2-RAD51 interaction and underline the importance of c-MET in DNA damage response.

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