scholarly journals Based on Bioinformatics Studies on the Effect of a lpha1H on Key Genes, Pathways in Bladder Cancer and lncRNA on Patient Prognosis

2022 ◽  
Author(s):  
Xing Wang ◽  
Jiandi Yu ◽  
Kun peng ◽  
Huali Wen ◽  
Renjie Wang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Cox Regression ◽  
Differentially Expressed ◽  
Lncrna Expression ◽  
Pathway Enrichment ◽  
Patient Prognosis ◽  
Upregulated Genes ◽  
Differential Genes

Abstract Objective: To analyze the differential genes, lncRNA, signaling pathway and patient prognosis of bladder cancer after alpha1H treatment.Methods: Sequencing data GSE172112 for patients in clinical trials with a new bladder cancer drug were downloaded from the GEO database, The bladder cancer tissues using the new drug alpha1H (alpha1-oleate) and placebo were analyzed in the R language, The differentially expressed genes were selected; Differential genes were analyzed for KEGG pathway enrichment using the DAVID database, To explore the effect of a lpha1H treatment on pathways in patients with bladder cancer; at the same time, lncRNA expression data from the Bladder Cancer (BLCA) dataset were also downloaded through the TCGA database, First, screening for differential lncRNA expression, The screening results were then analyzed by univariate Cox regression to initially screen for lncRNA associated with prognosis, The key lncRNA affecting the prognosis were further screened out, The prognostic model was also constructed using multivariate Cox regression analysis. Results: There yielded 394 significantly upregulated genes and 385 significantly downregulated genes in bladder cancer tissue after a lpha1H treatment. Through gene signaling pathway enrichment analysis, the upregulated genes were mainly enriched in the signaling pathways regulating the pluripotent line of stem cell cells, the TGF-signaling pathways, and the cell cycle. The downregulated genes were mainly enriched in the MAPK signaling pathway, phagosomes, and the TNF signaling pathway. After a lpha1H treatment, of 119 differentially expressed lncRNA, from the lnc2cancer database, two genes were found to be potentially associated with bladder cancer prognosis, and the final analysis confirmed the key lncRNA affecting prognosis. The results of survival analysis showed that high expression of LINC00152 unfavorable unfavorable patient prognosis and the new drug alpha1H reduces LINC00152 favors patient prognosis. Conclusion: Alpha1H can cure bladder cancer by regulating hallmark signaling, TGF-beta signaling, and LINC00152.

scholarly journals Ferroptosis-Related Long Non-Coding RNA Signature Predicts the Prognosis of Bladder Cancer

2021 ◽  
Author(s):  
Jian Hou ◽  
Zhenquan Lu ◽  
Xiaobao Cheng ◽  
Runan Dong ◽  
Yi Jiang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Signaling Pathway ◽  
Immune Cell ◽  
Cox Regression ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Assessment Model ◽  
Differentially Expressed ◽  
Immune Checkpoints

Abstract Background: Ferroptosis is an iron-dependent programmed cell death modality that may have a tumor suppressor function. Therefore, regulating ferroptosis in tumor cells could serve as a novel therapeutic approach. This article focuses on ferroptosis-associated long non-coding RNAs (lncRNAs) and their potential application as a prognostic model for bladder cancer (BCa). Methods: We retrieved bladder cancer-related transcriptome information and clinical information from the TCGA database and ferroptosis-related gene sets from the FerrDb database. Minimum absolute shrinkage and selection operator regression and Cox regression models were used to identify and develop predictive models and validate the models' accuracy. Finally, we explore the inter-regulatory relationships between ferroptosis-related genes and immune cell infiltration, immune checkpoints, and m6A methylation genes. Results: Kaplan-Meier analyses revealed 11 differentially expressed lncRNAs associated with poor BCa prognosis. This signature (AUC = 0.720) could potentially be utilized to predict BCa prognosis. Our risk assessment model outperformed traditional clinicopathological features in predicting BCa prognosis. Additionally, GSEA revealed immune and tumor-related pathways in individuals in the low-risk group. TCGA showed that the p53 signaling pathway，ferroptosis，Kaposi sarcoma−associated herpesvirus infection，IL−17 signaling pathway，MicroRNAs in cancer，TNF signaling pathway，PI3K−Akt signaling pathway and HIF−1 signaling pathway were significantly different from those in the high-risk group. Immune checkpoints, such as PDCD-1 (PD-1), CTLA4, and LAG3, were also differentially expressed between the two risk groups. m6A methylation-related genes were likewise significantly differentially expressed between the two risk groups.Conclusion: A new ferroptosis-associated lncRNAs signature on the prognosis of BCa patients will provide new ideas for the treatment and management of BCa patients.

scholarly journals Aberrant expression of long non-coding RNA in thyroid neoplasms

2019 ◽  
pp. 17-25
Author(s):  
В.Д. Якушина ◽  
А.С. Танас ◽  
А.В. Лавров
Keyword(s):  
Thyroid Cancer ◽  
Signaling Pathway ◽  
In Silico ◽  
Thyroid Nodules ◽  
Differentially Expressed ◽  
Follicular Variant ◽  
Aberrant Expression ◽  
Lncrna Expression ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Актуальность. Длинные некодирующие РНК (днРНК) при раке щитовидной железы плохо изучены; не известны днРНК, общие и специфичные для фолликулярного и классического вариантов папиллярного рака, не установлены днРНК, аберрантно экспрессированные при других основных субтипах злокачественных новообразований щитовидной железы, а также при доброкачественных новообразованиях. Цель исследования - определить днРНК, аберрантно экспрессированные при фолликулярной аденоме (ФА), фолликулярном раке (ФРЩЖ), фолликулярном и классическом вариантах папиллярного рака (ПРЩЖ), анапластическом раке (АРЩЖ) щитовидной железы. Методы. Проанализирована экспрессия днРНК по данным исследований на микрочипах (8 независимых экспериментов, доступных в GEO) и секвенирования РНК (PRJEB11591 и TCGA-THCA). Исследованы 246 образцов нормальной ткани щитовидной железы, 26 - ФА, 30 - ФРЩЖ, 181 - фолликулярного варианта ПРЩЖ, 481 - классического варианта ПРЩЖ и 49 - АРЩЖ. Для классического и фолликулярного вариантов ПРЩЖ выполнена валидация дифференциальной экспрессии in silico. Потенциальные биологические функции были оценены в результате анализа обогащения коэкспрессированных генов. Результаты. Определены днРНК, дифференциально экспрессированные при ФА, ФРЩЖ, фолликулярном и классическом вариантах ПРЩЖ и АРЩЖ. Выявлены 8 днРНК, экспрессия которых изменена во всех субтипах новообразований щитовидной железы, 22 - общих для ПРЩЖ, 32 - специфичных для классического варианта ПРЩЖ, 1 - специфичная для фолликулярного варианта ПРЩЖ, и 177 - специфичных для АРЩЖ. Статистически значимо дифференциально экспрессированных днРНК в ФРЩ по сравнению с ФА не выявлено. Ранее известные онкогенные и супрессорные днРНК NR2F1-AS1, LINC00511, SLC26A4-AS1, CRNDE, RMST впервые обнаружены в новообразованиях щитовидной железы. Выявленные днРНК предположительно вовлечены в клеточную адгезию, организацию экстрацеллюлярного матрикса, образование эндодермы, регуляцию клеточного цикла и митоза, полярности клеток, сигнальные пути VEGF и WNT. Выводы. Установлены общие и специфичные паттерны экспрессии днРНК в доброкачественных и злокачественных новообразованиях щитовидной железы. Background. Long non-coding RNA (lncRNA) in thyroid cancer are poorly investigated; no lncRNAs common and specific for the follicular and classical variants of papillary cancer, as well as no lncRNAs aberrantly expressed in benign nodules or other subtypes of thyroid cancer are established. The objective of the study is to determine long noncoding RNAs aberrantly expressed in follicular adenoma (FA), follicular carcinoma (FTC), follicular and classical variants of papillary carcinoma (PTC), anaplastic carcinoma (ATC). Methods. lncRNA expression was analyzed in dataset of Microarray (8 independent experiments available in GEO) and RNA-seq studies (PRJEB11591 and TCGA-THCA). In total, 246 samples of normal thyroid tissue, 26 FAs, 30 FTCs, 181 follicular variant PTCs, 481 classic variant PTCs and 49 ATCs were examined. In silico validation was performed. Potential biological functions were assessed by enrichment analysis of coexpressed genes. Results. LncRNAs differentially expressed in FA, FTC, follicular, and classical variants of PTC, and ATC are identified. There are 8 lncRNAs common for all investigated thyroid nodules, 22 common for PTC, 32 specific for classical PTC, 1 specific for follicular variant of PTC, and 177 specific for ATC. No lncRNA significantly differentially expressed in FTC compared to FA is identified. The previously described oncogenic and suppressor lncRNAs NR2F1-AS1, LINC00511, SLC26A4-AS1, CRNDE, RMST are detected in thyroid carcinomas for the first time. Identified lncRNA are putatively involved in cell adhesion, extracellular matrix organization, endoderm formation, VEGF signaling pathway, WNT signaling pathway and cell polarity, cell cycle and mitosis. Conclusion. The general and specific patterns of lncRNA expression in benign and malignant thyroid nodules are established.

scholarly journals Arginine Deiminase and Biotin Metabolism Signaling Pathways Play an Important Role in Human-Derived Serotype V, ST1 Streptococcus agalactiae Virulent Strain upon Infected Tilapia

Animals ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 849
Author(s):  
Yu Liu ◽  
Liping Li ◽  
Zhiping Luo ◽  
Rui Wang ◽  
Ting Huang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Streptococcus Agalactiae ◽  
Functional Annotation ◽  
Virulent Strain ◽  
Comprehensive Analysis ◽  
Arginine Deiminase ◽  
Differentially Expressed ◽  
Comprehensive Understanding ◽  
Protein Levels

Our previous study showed that human-derived Streptococcus agalactiae (serotype V) could infect tilapia, but the mechanism underlying the cross-species infection remains unrecognized. In this study, a multi-omics analysis was performed on human-derived S.agalactiae strain NNA048 (virulent to tilapia, serotype V, ST1) and human-derived S.agalactiae strain NNA038 (non-virulent to tilapia, serotype V, ST1). The results showed that 907 genes (504 up/403 down) and 89 proteins (51 up/38 down) were differentially expressed (p < 0.05) between NNA038 and NNA048. Among them, 56 genes (proteins) were altered with similar trends at both mRNA and protein levels. Functional annotation of them showed that the main differences were enriched in the arginine deiminase system signaling pathway and biotin metabolism signaling pathway: gdhA, glnA, ASL, ADI, OTC, arcC, FabF, FabG, FabZ, BioB and BirA genes may have been important factors leading to the pathogenicity differences between NNA038 and NNA048. We aimed to provide a comprehensive analysis of the human-derived serotype V ST1 S.agalactiae strains, which were virulent and non-virulent to tilapia, and provide a more comprehensive understanding of the virulence mechanism.

scholarly journals LINC00467 Promotes Tumor Progression via Regulation of the NF-kb Signal Axis in Bladder Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiawei Xiao ◽  
Lian Gong ◽  
Mengqing Xiao ◽  
Dong He ◽  
Liang Xiang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Animal Experiments ◽  
Bioinformatic Analysis ◽  
New Strategy ◽  
Patient Prognosis

PurposeLong non-coding RNAs (lncRNAs) play an important role in the occurrence and development of bladder cancer, but the underlying molecular mechanisms remain largely unknown. In this study, we found that LINC00467 was significantly highly expressed in bladder cancer through bioinformatic analysis. The present study aimed to explore the role of LINC00467 in bladder cancer and its possible underlying molecular mechanisms.MethodsThe expression of LINC00467 was obtained from GEO (GSE31189), the TCGA database, and qRT-PCR. The role of LINC00467 in bladder cancer was assessed both in vitro and in vivo. RIP, RNA pulldown, and CO-IP were used to demonstrate the potential mechanism by which LINC00467 regulates the progression of bladder cancer.ResultsThrough the analysis of GEO (GSE133624) and the TCGA database, it was found that LINC00467 was highly expressed in bladder cancer tissues and that the expression of LINC00467 was significantly negatively correlated with patient prognosis. Cell and animal experiments suggest that LINC00467 promotes the proliferation and invasion of bladder cancer cells. On the one hand, LINC00467 can directly bind to NF-kb-p65 mRNA to stabilize its expression. On the other hand, LINC00467 can directly bind to NF-kb-p65 to promote its translocation into the nucleus to activate the NF-κB signaling pathway, which promotes the progression of bladder cancer.ConclusionsLINC00467 is highly expressed in bladder cancer and can promote the progression of bladder cancer by regulating the NF-κB signaling pathway. Therefore, targeting LINC00467 is very likely to provide a new strategy for the treatment of bladder cancer and for improving patient prognosis.

scholarly journals Discovery and Validation of Circulating EVL mRNA as a Prognostic Biomarker in Pancreatic Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Yan Du ◽  
Kai Yao ◽  
Qingbo Feng ◽  
Feiyu Mao ◽  
Zechang Xin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Mrna Expression ◽  
Cox Regression ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Cancer Type ◽  
Mrna Levels ◽  
Plasma Samples ◽  
Patient Prognosis

Background. Circulating plasma mRNAs can be analyzed to identify putative cancer biomarkers. This study was conducted in an effort to detect plasma mRNA biomarkers capable of predicting pancreatic cancer (PACA) patient prognosis. Material and Methods. First, prognostic mRNAs that were differentially expressed in PACA in The Cancer Genome Atlas (TCGA) were established, after which microarray expression profiles from PACA patient plasma samples were utilized to specifically identify potential prognostic plasma mRNA biomarkers associated with this cancer type. In total, plasma samples were then collected from 79 PACA patients and 19 healthy controls to confirm differential mRNA expression via qPCR, while Kaplan–Meier analyses were used to examine the link between mRNA expression and patient overall survival. Results. In total, three prognostic differentially expressed genes were identified in PACA patient plasma samples, including SMAP2, PTPN6, and EVL (Ena/VASP-like). Plasma EVL levels were confirmed via qPCR to be correlated with tumor pathology p < 0.01 , while the overall survival of patients with low plasma EVL levels was poor p < 0.01 . Multivariate Cox regression analyses further confirmed that plasma EVL levels were independent predictors of PACA patient prognosis. Conclusion. We found that PACA is associated with the downregulation of plasma EVL mRNA levels, indicating that this mRNA may be a viable biomarker associated with patient prognosis.

scholarly journals Identification of a nine ferroptosis-related lncRNA prognostic signature for lung adenocarcinoma

2021 ◽  
Author(s):  
Xiwen Tong ◽  
Yujiao Zhang ◽  
Guodong Yang ◽  
Guanghui Yi
Keyword(s):  
Lung Adenocarcinoma ◽  
Signaling Pathways ◽  
Cox Regression ◽  
Risk Group ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Rank Test ◽  
Lymph Node Status ◽  
Prognostic Signature ◽  
Test Set

Abstract Background Recently, mounting of studies has shown that lncRNA affects tumor progression through the regulation of ferroptosis. The current study aims to construct a robust ferroptosis-related lncRNAs signature to increase the predicted value of lung adenocarcinoma (LUAD) by bioinformatics analysis. Methods The transcriptome data were abstracted from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs were screened by comparing 535 LAUD tissues with 59 adjacent non-LAUD tissues. Univariate Cox regression, lasso regression, multivariate Cox regression were conducted to design a ferroptosis-related lncRNA signature. This signature’s prognosis was verified by the log-rank test of Kaplan-Meier curve and the area under curve (AUC) of receiver operating characteristic (ROC) in train set, test set, and entire set. Furthermore, univariate and multivariate Cox regression were used to analyze its independent prognostic ability. The relationship of the ferroptosis-linked lncRNAs' expression and clinical variables was demonstrated by Wilcoxon rank-sum test and Kruskal-Wallis test. Gene set enrichment analysis (GSEA) was performed to signaling pathways it may involve. Results 1224 differentially expressed lncRNAs were idendified, of which 195 are ferroptosis-related lncRNAs. A nine ferroptosis-related lncRNAs (AC099850.3, NAALADL2-AS2, AL844908.1, AL365181.2, SMIM25, FAM83A-AS1, LINC01116, AL049836.1, C20orf197) prognostic signature was constucted. This model's prognosis in the high-risk group is obviously worse than that of the low-risk group in train set, test set, and entire set. The AUC of ROC predicting the three years survival in the train set, test set, and entire set was 0.754, 0.716, and 0.738, respectively. Moreover, the designed molecular signature was found to be an independent prognostic variable. The expression of these lncRNAs and the lncRNA signature are related to clinical stage, T stage, Lymph-node status, distant metastasis. Finally, GSEA analysis results show that the signature is involved in eight tumor-related and metabolism-related signaling pathways Conclusion The current study constructed, validated, and evaluated a nine ferroptosis-related lncRNA signature which can independently be used to predict the prognosis of LAUD patients, and may become a new therapeutic target.

scholarly journals Integrated analysis of autophagy-related genes(ATGs) reveals the prognostic value of oral squamous cell carcinoma

2020 ◽  
Author(s):  
Guangzhao Huang ◽  
Zhi-yun Li ◽  
Yu Rao ◽  
Xiao-zhi Lv
Keyword(s):  
Survival Analysis ◽  
Signaling Pathway ◽  
Risk Score ◽  
Prognostic Value ◽  
Risk Model ◽  
Cox Regression ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Integrated Analysis ◽  
Score Model

Abstract Background: Increasing evidence demonstrated that autophagy paly a crucial role in initiation and progression of OSCC. The aim of this study was to explore the prognostic value of autophagy-related genes(ATGs) in patients with OSCC. RNA-seq and clinical data were downloaded from TCGA database following extrating ATGs expression profiles. Then, differentially expressed analysis was performed in R software EdgeR package, and the potential biological function of differentially expressed ATGs were explored by GO and KEGG enrichment analysis. Furthermore, a risk score model based on ATGs was constructed to predict the overall survival. Moreover, univariate, multivariate cox regression and survival analysis were used to select autophagy related biomarkers which were identified by RT-qPCR in OSCC cell lines, OSCC tissues and matched normal mucosal tissues. Results: Total of 232 ATGs were extrated and 37 genes were differentially expressed in OSCC. GO and KEGG analysis indicated that these differentially expressed genes were mainly located in autophagosome membrane, and associated with apoptosis, platinum drug resistance, ErbB signaling pathway and TNF signaling pathway. Furthermore, a risk score model including 9 variables was constructed and subsequently identified with univariate, multivariate cox regression, survival analysis and Receiver Operating Characteristic curve(ROC). Moreover, ATG12 and BID were identified as potential autophagy related biomakers. Conclusion: This study successfully constructed a risk model to predict the prognosis of patients with OSCC, and the risk score may be as a independent prognostic biomarker in OSCC. ATG12 and BID were identified as potential biomarkers in tumor diagnosis and treatment of OSCC.

scholarly journals Long non-coding RNA, LINC01614 as a potential biomarker for prognostic prediction in breast cancer

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7976 ◽  
Author(s):  
Yaozong Wang ◽  
Baorong Song ◽  
Leilei Zhu ◽  
Xia Zhang
Keyword(s):  
Breast Cancer ◽  
Prognostic Value ◽  
Cox Regression ◽  
Expression Profiles ◽  
Differential Expression Analysis ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Lncrna Expression ◽  
Normal Tissues ◽  
Potential Biomarker

Background Dysregulated long non-coding RNAs (lncRNAs) may serve as potential biomarkers of cancers including breast cancer (BRCA). This study aimed to identify lncRNAs with strong prognostic value for BRCA. Methods LncRNA expression profiles of 929 tissue samples were downloaded from TANRIC database. We performed differential expression analysis between paired BRCA and adjacent normal tissues. Survival analysis was used to identify lncRNAs with prognostic value. Univariate and multivariate Cox regression analyses were performed to confirm the independent prognostic value of potential lncRNAs. Dysregulated signaling pathways associated with lncRNA expression were evaluated using gene set enrichment analysis. Results We found that a total of 398 lncRNAs were significantly differentially expressed between BRCA and adjacent normal tissues (adjusted P value <= 0.0001 and |logFC| >= 1). Additionally, 381 potential lncRNAs were correlated Overall Survival (OS) (P value < 0.05). A total of 48 lncRNAs remained when differentially expressed lncRNAs overlapped with lncRNAs that had prognostic value. Among the 48 lncRNAs, one lncRNA (LINC01614) had stronger prognostic value and was highly expressed in BRCA tissues. LINC01614 expression was validated as an independent prognostic factor using univariate and multivariate analyses. Higher LINC01614 expression was observed in several molecular subgroups including estrogen receptors+, progesterone receptors+ and human epidermal growth factor receptor 2 (HER2)+ subgroup, respectively. Also, BRCA carrying one of four gene mutations had higher expression of LINC01614 including AOAH, CIT, HER2 and ODZ1. Higher expression of LINC01614 was positively correlated with several gene sets including TGF-β1 response, CDH1 signals and cell adhesion pathways. Conclusions A novel lncRNA LINC01614 was identified as a potential biomarker for prognosis prediction of BRCA. This study emphasized the importance of LINC01614 and further research should be focused on it.

scholarly journals INHBB Is a Novel Prognostic Biomarker Associated with Cancer-Promoting Pathways in Colorectal Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Jinpeng Yuan ◽  
Aosi Xie ◽  
Qiangjian Cao ◽  
Xinxin Li ◽  
Juntian Chen
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Disease Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Receptor Interaction

Background. Inhibin subunit beta B (INHBB) is a protein-coding gene that participated in the synthesis of the transforming growth factor-β (TGF-β) family members. The study is aimed at exploring the clinical significance of INHBB in patients with colorectal cancer (CRC) by bioinformatics analysis. Methods. Real-time PCR and analyses of Oncomine, Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) databases were utilized to evaluate the INHBB gene transcription level of colorectal cancer (CRC) tissue. We evaluated the INHBB methylation level and the relationship between expression and methylation levels of CpG islands in CRC tissue. The corresponding clinical data were obtained to further explore the association of INHBB with clinical and survival features. In addition, Gene Set Enrichment Analysis (GSEA) was performed to explore the gene ontology and signaling pathways of INHBB involved. Results. INHBB expression was elevated in CRC tissue. Although the promoter of INHBB was hypermethylated in CRC, methylation did not ultimately correlate with the expression of INHBB. Overexpression of INHBB was significantly and positively associated with invasion depth, distant metastasis, and TNM stage. Cox regression analyses and Kaplan-Meier survival analysis indicated that high expression of INHBB was correlated with worse overall survival (OS) and disease-free survival (DFS). GSEA showed that INHBB was closely correlated with 5 cancer-promoting signaling pathways including the Hedgehog signaling pathway, ECM receptor interaction, TGF-β signaling pathway, focal adhesion, and pathway in cancer. INHBB expression significantly promoted macrophage infiltration and inhibited memory T cell, mast cell, and dendritic cell infiltration. INHBB expression was positively correlated with stromal and immune scores of CRC samples. Conclusion. INHBB might be a potential prognostic biomarker and a novel therapeutic target for CRC.

Whole Blood Transcriptional Profiling of DLBCL At Diagnosis: Evidence of Systemic Changes Altering T-Cell Signaling Pathways

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2435-2435
Author(s):  
Delphine Rossille ◽  
Céline Pangault ◽  
Xavier Cahu ◽  
Thierry Lamy ◽  
Burgun Anita ◽  
...  
Keyword(s):  
Gene Expression ◽  
Healthy Volunteers ◽  
Signaling Pathways ◽  
Differentially Expressed Genes ◽  
Whole Blood ◽  
Transcriptional Profiling ◽  
The Body ◽  
Differentially Expressed ◽  
Cytokine Signaling ◽  
Upregulated Genes

Abstract Abstract 2435 DLBCLs are the most prevalent lymphomas in adults and great advances have been made in understanding molecular effects on tumor cells as well as tissue environment, leading to determining gene prognosis signatures using transcriptional profiling techniques. As blood cells interact with cells in almost all tissues in the body, blood-derived total RNA gene expressions have been investigated for the past years including for solid cancers [Clin Cancer Res. 2006:3374.], infections [Nature 2010;446:973.] and autoimmune disorders [Genes Immun. 2010;11:269., Immunity 2008;29:150.]. Blood-based microarray approaches were able to identify differentially expressed genes distinguishing patients from healthy volunteers. Interested in the potential of this noninvasive and easy-to-use technique, we hypothesized that aggressive DLBCLs at diagnosis cause molecular perturbations on the whole blood allowing identifying gene expression differentiation compared to healthy controls. Whole blood was collected into PAXgene™ Blood RNA tubes ensuring blood stabilization and sent within 24 hours to be stored at −80°C before extraction. Our study involved high-quality RNA samples from 75 DLBCL patients taken at diagnosis prior to any anti-cancer treatment and 87 healthy volunteers, sex and gender matched. All patients were less than 60 and enrolled in a multicentric & prospective clinical trial for aggressive form of DLBCL, GOELAMS 075, which compares the autologous stem cell treatment to regular R-CHOP procedure. The median age was 52 for patients and 48 for controls. Gene expression profiling (GEP) was assessed using Affymetrix GeneChip® Human Exon 1.0 ST arrays. Unsupervised hierarchical clustering analysis (HCA) distinguished DLBCLs from controls. Two gene lists were identified based on HCA (Figure 1): listA consisted in 3,323 upregulated genes for a subgroup of patients and inversely, listB in 2,966 upregulated genes for controls. Canonical pathways were generated for both lists for genes meeting p<5% and FC >1.2 through the use of IPA (Ingenuity® Systems). The upregulated genes for patients (listA) were found associated with cytokine signaling pathways (Interleukins, NF-κB) while the down-regulated genes (listB) were implicated in T lymphocytes signaling pathways. Further investigations of the dataset by univariate analysis (Mann-Whitney test, FDR<5%, FC >1.5) found 1047 differentially expressed genes, confirming the systemic alteration. A set of 20 genes, selected as the best predictive genes for which the misclassification error rate is minimal, was able to discriminate DLBCLs from control samples (sensitivity= 88% & specificity=95%). No correlation was found between genes and biological parameters such as hemoglobin, leucocytes, lymphocytes, platelets or polynuclear neutrophils. The down-regulated genes were located in the nucleus and involved in transcription deregulation, DNA repair and apoptosis. Upregulated genes were related to the immune response as well as the inflammatory response with for instance S100 proteins which are implicated in myeloid-derived suppressor cell biology. Conclusion: Despite the complex mixture of cell types in blood, whole blood has shown strong systemic perturbations in DLBCLs at diagnosis. Biological investigation indicated an over-expression of the inflammation and immune responses combined to perturbations of the T-lymphocyte pattern. Our findings concerning inflammation-related gene expression including NF-κB activation and upregulated cytokine transcripts, with for instance IL-1, IL-6 & IL-10, invite us to determine whether a specific DLBCL-induced inflammation process exists compared to other nonmalignant diseases [Clin Microbiol Rev. 2002 Jul; 15(3):414-29]. Comparison to other lymphoma and inflammatory diseases as well as with tumor status are under way allowing to better characterizing DLBCL-specific biomarkers. These results shed new lights on DLBCL biology deciphering disease's heterogeneity at the RNA whole blood level. They encourage us to investigate whole blood GEP for prognosis and as a new parameter useful for disease classification. Disclosures: No relevant conflicts of interest to declare.

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