scholarly journals RNA Sequencing-Based Identification of Ganglioside GD2-Positive Cancer Phenotype

Biomedicines ◽  
2020 ◽  
Vol 8 (6) ◽  
pp. 142 ◽  
Author(s):  
Maxim Sorokin ◽  
Irina Kholodenko ◽  
Daniel Kalinovsky ◽  
Tatyana Shamanskaya ◽  
Igor Doronin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Sequencing ◽  
Human Tumor ◽  
Gene Expression Signature ◽  
Sequencing Data ◽  
Biopsy Material ◽  
Ganglioside Gd2 ◽  
Expression Signature ◽  
Ganglioside Biosynthesis ◽  
Tumor Phenotypes

The tumor-associated ganglioside GD2 represents an attractive target for cancer immunotherapy. GD2-positive tumors are more responsive to such targeted therapy, and new methods are needed for the screening of GD2 molecular tumor phenotypes. In this work, we built a gene expression-based binary classifier predicting the GD2-positive tumor phenotypes. To this end, we compared RNA sequencing data from human tumor biopsy material from experimental samples and public databases as well as from GD2-positive and GD2-negative cancer cell lines, for expression levels of genes encoding enzymes involved in ganglioside biosynthesis. We identified a 2-gene expression signature combining ganglioside synthase genes ST8SIA1 and B4GALNT1 that serves as a more efficient predictor of GD2-positive phenotype (Matthews Correlation Coefficient (MCC) 0.32, 0.88, and 0.98 in three independent comparisons) compared to the individual ganglioside biosynthesis genes (MCC 0.02–0.32, 0.1–0.75, and 0.04–1 for the same independent comparisons). No individual gene showed a higher MCC score than the expression signature MCC score in two or more comparisons. Our diagnostic approach can hopefully be applied for pan-cancer prediction of GD2 phenotypes using gene expression data.

scholarly journals An mRNA expression-based signature for oncogene-induced replication-stress

2021 ◽  
Author(s):  
Sergi Guerrero Llobet ◽  
Arkajyoti Bhattacharya ◽  
Marieke Everts ◽  
Bert van der Vegt ◽  
Rudolf S.N. Fehrmann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Rna Sequencing ◽  
Cell Lines ◽  
Gene Expression Signature ◽  
B Cell Lymphoma ◽  
Replication Stress ◽  
Sequencing Data ◽  
Cancer Subtypes ◽  
Expression Signature

ABSTRACTBackgroundOncogene-induced replication stress characterizes many aggressive cancers, including triple-negative breast cancer (TNBC). Several drugs are being developed that target replication stress, although it is unclear how tumors with high levels of replication stress can be identified. We aimed to develop a gene expression signature of oncogene-induced replication stress.MethodsTNBC and non-transformed RPE1-TP53wt and RPE1-TP53mut cell lines were engineered to overexpress the oncogenes CDC25A, CCNE1 or MYC. DNA fiber analysis was used to measure replication kinetics. Analysis of RNA sequencing data of cell lines and patient-derived tumor samples (TCGA n=10,592) was used to identify differential gene expression. Immunohistochemical validation was conducted on breast cancer samples (n=330).ResultsRNA sequencing revealed 52 commonly upregulated genes after induction of CDC25A, CCNE1 or MYC in our cell line panel. Integration with gene expression data of TGCA samples with amplification of replication stress-inducing oncogenes (CDC25A, CCNE1, MYC, CCND1, MYB, MOS, KRAS, ERBB2, and E2F1), yielded a six-gene signature of oncogene-induced replication stress (NAT10, DDX27, ZNF48, C8ORF33, MOCS3, and MPP6). Expression of NAT10 in breast cancer samples was correlated with phospho-RPA (R=0.451, p=1.82×10−20) and γH2AX (R=0.304, p=2.95×10−9). Applying the oncogene-induced replication stress signature to patient samples (TCGA n=8,862 and GEO n=13,912) defined the replication stress landscape across 27 tumor subtypes, and identified diffuse large B cell lymphoma, ovarian cancer, TNBC and colorectal carcinoma as cancer subtypes with high levels of oncogene-induced replication stress.ConclusionWe developed a gene expression signature of oncogene-induced replication stress, which may facilitate patient selection for agents that target replication stress.

scholarly journals Identification of a Gene Signature Associated to Treatment Response to Palbociclib in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5666-5666
Author(s):  
Angelique Bruyer ◽  
Alboukadel Kassambara ◽  
Paul Anziani ◽  
Donia El Bahlagui ◽  
Nicolas Robert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Multiple Myeloma ◽  
Rna Sequencing ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Gene Expression Signature ◽  
G1 Arrest ◽  
Expression Signature

Abstract Background: Inpatients with relaspsed/refractoryMultiple Myeloma (MM), outcomes are far from optimal, especially in patients refractory to current treatments Recent studies and clinical trials have highlighted the therapeutic potential of Palbociclib, a CDK4/6 inhibitor, in various cancers including MM. Deregulation of CDK4/6 is involved in the loss of cell cycle control in MM. Response to Palbociclib combined with bortezomib and dexamethasone was acquired in 20% of the relapsed/refractory MM patients, suggesting that biomarkers to identify patients that could benefit from this treatment are needed. Additional studies are required to understand the biological pathways associated with sensitivity or resistance of MM cells to Palbociclib. Methods: 14 human MM cell lines and 12 primary MM samples were tested for response to Palbociclib treatment. The concentration required to inhibit growth by 50% (IC50) was calculated. Gene expression signature associated with multiple myeloma response to Palbociclib, as well as, genes deregulated by the treatment have been analyzed using microarray and RNA-sequencing methods. Results: Palbociclib had an heterogeneous in vitro activity among the 14 human myeloma cell lines tested, which aggregated into three groups based on the distribution of the IC50 values: sensitive (n = 5, IC50: 0.2 - 0.3µM), intermediate (n = 3, IC50: 0.5 - 0.7µM) or more resistant group (n = 6, IC50: 0.9 - 2.4µM). The same holds true when testing the Palbociclib on primary multiple myeloma samples. The evaluation of the Palbociclib effect on cell cycle progression and the induction of the apoptosis, reveals that Palbociclib is essentially cytostatic, inducing prolonged G1 arrest in sensitive cell lines with a strong reduction of the percentage of cells in S phase. To better understand the molecular mechanisms associated with Palbociclib response, we identified a gene expression signature correlated with the response in both MM cell lines and primary myeloma cells from patients. Additionally, we have analyzed differentially expressed genes after Palbociclib treatment in human MM cell lines using RNA sequencing (n = 4). The physiological role of the downregulated genes after Palbociclib treatment is associated with cell cycle, mitosis and E2F mediated regulation of DNA replication. Significantly upregulated genes, after Palbociclib treatment, were enriched in genes encoding proteins involved in glutathione synthesis and recycling, and biological oxidations. Conclusion: Altogether, our data demonstrated a high heterogeneity in the response of MM cells to Palbociclib. We identified a gene expression signature associated with Palbociclib response in MM. These genes could help to identify MM patients that could benefit from Palbociclib treatment and provide novel targets for efficient combination therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature

2017 ◽  
Vol 13 (1) ◽  
pp. e1006143 ◽  
Author(s):  
Coralie Viollet ◽  
David A. Davis ◽  
Shewit S. Tekeste ◽  
Martin Reczko ◽  
Joseph M. Ziegelbauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Sequencing ◽  
Gene Expression Signature ◽  
Kaposi Sarcoma ◽  
Herpesvirus Infection ◽  
Expression Signature

Discovering new targeted therapies for BRAF mutant-like colorectal cancers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3623-3623
Author(s):  
F. Anthony San Lucas ◽  
Scott Kopetz ◽  
Paul A. Scheet ◽  
Eduardo Vilar Sanchez
Keyword(s):  
Gene Expression ◽  
Systems Biology ◽  
Rna Sequencing ◽  
Expression Profiles ◽  
Gene Expression Signature ◽  
The Cancer Genome Atlas ◽  
Colorectal Cancers ◽  
Expression Data ◽  
Wild Type ◽  
Sequencing Data

3623 Background: Approximately 10% of colorectal cancers (CRCs) harbor a BRAF mutation (BRAFm). Patients with BRAFm tumors have poor prognosis and are a therapeutic challenge. A BRAFm gene expression signature has been communicated (Popovici et al, JCO 2012), which can identify BRAFm tumors as well as BRAF wild-type tumors that display a similar expression pattern. Collectively, these tumors are termed BRAFm-like. Our goal was to validate this signature using next-generation sequencing and to discover novel therapies for BRAFm-like CRCs using a systems biology approach. Methods: We developed a semi-automated workflow that integrates publicly available tools named the Cancer In-silico Drug Discovery (CIDD). To validate the BRAFm-like signature, we used CIDD to analyze the CRC dataset from the The Cancer Genome Atlas Network (TCGA). Samples were stratified on BRAFm status using exome-sequencing, and expression profiles were inferred from RNA-sequencing. We matched expression profiles with drug-induced signatures inferred from the Connectivity Map (CMap) – a systems biology tool that contains expression data of cell lines treated with 1,500 compounds. CIDD statistically ranks candidate compounds and annotates them to pathways using public databases. Results: When applied to TCGA RNA-sequencing data, a classifier based on the BRAFm-like signature resulted in 93.3% sensitivity and 83.5% specificity for detecting BRAFm samples. When applied to Agilent gene expression data, this resulted in 80% sensitivity and 91.1% specificity. 41% of KRAS-mutated samples and 14% of double wild-type samples were predicted to be BRAFm-like. 100% of MSI-high and 18% of MSS samples were predicted to be BRAFm-like. Compounds near the top of our drug rankings include Gefitinib and MG-262 a proteasome inhibitor. Conclusions: We have validated the BRAFm-like signature using RNA-sequencing and Agilent expression data from the TCGA, and showed a high degree of robustness across technologies. We have identified EGFR and proteasome inhibitors as potential compounds to target BRAFm-like CRCs.

scholarly journals Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma

2019 ◽  
Vol 37 (3) ◽  
pp. 190-201 ◽  
Author(s):  
Daisuke Ennishi ◽  
Aixiang Jiang ◽  
Merrill Boyle ◽  
Brett Collinge ◽  
Bruno M. Grande ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Rna Sequencing ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
Gene Expression Signature ◽  
B Cell Lymphoma ◽  
Distinct Subgroup ◽  
Expression Signature ◽  
Germinal Center B Cell

Purpose High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH- BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression. Patients and Methods We analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH- BCL2, to define a gene expression signature that distinguishes HGBL-DH/TH- BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data. Results We developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH- BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy compared with DHITsig-negative patients (5-year time to progression rate, 57% and 81%, respectively; P < .001), irrespective of HGBL-DH/TH- BCL2 status. The prognostic value of DHITsig was confirmed in an independent validation cohort. DHITsig-positive tumors are biologically characterized by a putative non–light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification. A new NanoString assay (DLBCL90) recapitulated the prognostic significance and RNA sequencing assignments. Validating the association with HGBL-DH/TH- BCL2, 11 of 25 DHITsig-positive–transformed follicular lymphomas were classified as HGBL-DH/TH- BCL2 compared with zero of 50 in the DHITsig-negative group. Furthermore, the DHITsig was shared with the majority of B-cell lymphomas with high-grade morphology tested. Conclusion We have defined a clinically and biologically distinct subgroup of tumors within GCB-DLBCL characterized by a gene expression signature of HGBL-DH/TH- BCL2. This knowledge has been translated into an assay applicable to routinely available biopsy samples, which enables exploration of its utility to guide patient management.

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