Transcriptomic Analysis Identifies Complement Component 3 as a Potential Predictive Biomarker for Chemotherapy Resistance in Colorectal Cancer

Objective: 5-fluorouracil- and oxaliplatin-based FOLFOX regimens are mainstay chemotherapeutics for colorectal cancer (CRC) but drug resistance represents a major therapeutic challenge. To improve patient survival, there is a need to identify resistance genes to better understand the mechanisms underlying chemotherapy resistance.Methods: Transcriptomic datasets were retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and combined with our own microarray data. Weighted gene co-expression network analysis (WGCNA) was used to dissect the functional networks and hub genes associated with FOLFOX resistance and cancer recurrence. We then conducted analysis of prognosis, profiling of tumor infiltrating immune cells, and pathway overrepresentation analysis to comprehensively elucidate the biological impact of the identified hub gene in CRC.Results: WGCNA analysis identified the complement component 3 (C3) gene as the only hub gene associated with both FOLFOX chemotherapy resistance and CRC recurrence after FOLFOX chemotherapy. Subsequent survival analysis confirmed that high C3 expression confers poor progression-free survival, disease-free survival, and recurrence-free survival. Further correlational analysis revealed significant negative association of C3 expression with sensitivity to oxaliplatin, but not 5-fluorouracil. Moreover, in silico analysis of tumor immune cell infiltration suggested the change of C3 expression could affect tumor microenvironment. Finally, gene set enrichment analysis (GSEA) revealed a hyperactivation of pathways contributing to invasion, metastasis, lymph node spread, and oxaliplatin resistance in CRC samples with C3 overexpression.Conclusion: Our results suggest that high C3 expression is a debilitating factor for FOLFOX chemotherapy, especially for oxaliplatin sensitivity, and C3 may represent a novel biomarker for treatment decision of CRC.

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CLCA1 Has a Prognostic Indicator for the Colorectal Cancer by Weighted Gene Co-Expression Network Analysis

10.21203/rs.3.rs-209748/v1 ◽

2021 ◽

Author(s):

jiajng lin ◽

lingzhi yang ◽

suyong lin ◽

zhihua chen ◽

shaoqin chen

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Colon Cancer ◽

Network Analysis ◽

Mrna Expression ◽

Disease Free Survival ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Cancer Tissue ◽

Hub Gene

Abstract Colorectal cancer (CRC) has become the second most common digestive tract tumor. Even though the means to treat colon cancer have improved, patients prognosis is low due to the lack of accurate molecular targets. Hence, it urgently demanded better biomarkers for prognosis and progression of colon cancer. This study explores the hub gene associated with the prognosis of colorectal cancer and further analyzes the hub gene function. In this study, all genes mRNA expression data were from the cancer genome atlas (TCGA) colon cancer database and the Gene Expression Omnibus (GEO). These databases were used to screen the differentially expressed co-genes between colon cancer tissue and normal tissue. Weighted Gene Co-expression Network Analysis screened out a total of 103 differential co-expression genes (WGCNA). According to the R cluster profile package annotation analysis, these genes biological functions mainly concentrate on energy metabolism. Moreover, in the protein-protein interaction (PPI) network, the CytoHubba plugin of Cytoscape was used to screen out ten genes (CLCA1, ZG16, GUCA2B, GUCA2A, CLCA4, SLC26A3, MS4A12, GCG, SI, and NR1H4). According to the survival analysis results, high expression of CLCA1has better overall survival and disease-free survival in patients with CRC. Simultaneously, the mRNA expression of CLCA1 in normal tissues was higher than that in CRC tissues. Besides, there were significant differences in the expression of CLCA1 in pathological stage, T stage, and M stage. By using a gene set enrichment analysis, we found several considerable enrichment pathways in the high-groups. CIBERSORT analysis for the proportion of TICs revealed that B-cell naive, dendritic cells, plasma cells, and CD4+ T cells were positively correlated with CLCA1 expression, suggesting that CLCA1 might be responsible for the preservation of immune-dominant status for TME. Finally, in the Human Protein Atlas (HPA) database, the protein level of CLCA1 in the colorectal cancer samples decreased, consistent with the down-regulation of the mRNA expression level CLCA1. To sum up, by integrating WGCNA with differential gene expression analysis, this research generated a significant survival correlative gene called CLCA1 that can predict prognosis prediction in colon cancer.

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

BioMed Research International ◽

10.1155/2020/6909672 ◽

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.

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High preoperative levels of circulating SFRP5 predict better prognosis in colorectal cancer patients

Future Oncology ◽

10.2217/fon-2020-0356 ◽

2020 ◽

Vol 16 (31) ◽

pp. 2499-2509

Author(s):

Chandra Kirana ◽

Eric Smith ◽

Doan T Ngo ◽

Markus I Trochsler ◽

Peter J Hewett ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Value ◽

Disease Free Survival ◽

Normal Mucosa ◽

The Cancer Genome Atlas ◽

Free Survival ◽

Cancer Genome Atlas ◽

Colorectal Cancer Patients ◽

Diagnostic And Prognostic Value

The purpose of this research was to investigate the diagnostic and prognostic value of circulating SFRP5 (cSFRP5) in colorectal cancer (CRC). We evaluated preoperative cSFRP5 levels in CRC patients and controls (n = 208). We found significantly higher cSFRP5 levels in CRC patients compared with non-CRC controls (p < 0.001). Levels of cSFRP5 were significantly lower in CRC patients with either vascular invasion (p = 0.001) or liver metastasis (p = 0.016). High cSFRP5 levels were associated with longer disease-free survival in both univariate (p = 0.024) and multivariate (p = 0.015) analyses. Analysis of an independent tissue cohort from The Cancer Genome Atlas database revealed significantly lower SFRP5 RNA expression in CRC tumor tissue compared with adjacent normal mucosa (n = 590 vs 47; p < 0.0001). Our findings confirm the role of cSFRP5 as a physiologic tumor suppressor and demonstrate its potential diagnostic and prognostic value in CRC.

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Association Between Hypoxia-Inducible Factor-2α (HIF-2α) Expression and Colorectal Cancer and Its Prognostic Role: a Systematic Analysis

Cellular Physiology and Biochemistry ◽

10.1159/000491806 ◽

2018 ◽

Vol 48 (2) ◽

pp. 516-527 ◽

Cited By ~ 9

Author(s):

Susu Han ◽

Tao Huang ◽

Wen Li ◽

Shanshan Liu ◽

Wei Yang ◽

...

Keyword(s):

Colorectal Cancer ◽

Sequential Analysis ◽

Disease Free Survival ◽

B Cell Lymphoma ◽

The Cancer Genome Atlas ◽

Trial Sequential Analysis ◽

Good Survival ◽

Low Grade ◽

Prognostic Role ◽

Free Survival

Background/Aims: Although some studies showed that HIF-2α expression was correlated with an unfavorable prognosis in colorectal cancer (CRC), the prognostic results remain conflicting in CRC. The present study was performed to evaluate the association between HIF-2α expression and the clinicopathological features of this disease and to examine the potential prognostic role of HIF-2α expression in CRC. Methods: Pooled odds ratios (ORs) or hazard ratios (HRs) were calculated from available publications, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. Trial sequential analysis (TSA) was used to estimate the required sample information. Results: HIF-2α protein expression was more frequent in CRC than in normal colonic tissues (OR = 150.49, P < 0.001), higher in male than female CRC patients (OR = 1.47, P = 0.008), and lower in high-grade than low-grade CRC (OR = 0.49, P = 0.029). TSA verified the reliability of the above results. HIF-2α expression was not linked to the prognosis of CRC in overall survival (OS), disease-specific survival (DSS), metastasis-free survival, and relapse-free survival, and no significant correlation was found between HIF-2α alteration and OS or disease-free survival (DFS) of CRC. Expression of both HIF-2α and vascular endothelial growth factor (VEGFA, VEGFB, or VEGFC) was associated with a poor metastasis-free survival of CRC (HR = 6.95, HR = 113.51, and HR = 8.11, respectively). No association was observed between HIF-2α expression and DFS in other cancers, but HIF-2α expression was correlated with a worse DFS of CRC (HR = 1.23, P = 0.037). Moreover, HIF-2α expression was linked to a good survival benefit in some cancers (B-cell lymphoma and lung adenocarcinoma: OS, multiple myeloma: DSS, breast cancer: distant metastasis-free survival, liposarcoma: distant recurrence-free survival) (all HRs < 1, Ps < 0.05). Conclusions: HIF-2α expression may be associated with the carcinogenesis of CRC, which is higher in males than in females, negatively linked to tumor differentiation, and correlated with a worse DFS of CRC. Additional prospective studies are needed.

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CACNA1C is a prognostic predictor for patients with ovarian cancer

Journal of Ovarian Research ◽

10.1186/s13048-021-00830-z ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Xiaohan Chang ◽

Yunxia Dong

Keyword(s):

Ovarian Cancer ◽

Cox Regression ◽

Disease Free Survival ◽

Cancer Genome ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Signal Pathways ◽

Regression Analyses ◽

Free Survival ◽

Prognostic Predictor

Abstract Background CACNA1C, as a type of voltage-dependent calcium ion transmembrane channel, played regulatory roles in the development and progress of multiple tumors. This study was aimed to analyze the roles of CACNA1C in ovarian cancer (OC) of overall survival (OS) and to explore its relationships with immunity. Methods Single gene mRNA sequencing data and corresponding clinical information were obtained from The Cancer Genome Atlas Database (TCGA) and the International Cancer Genome Consortium (ICGC) datasets. Gene set enrichment analysis (GSEA) was used to identify CACNA1C-related signal pathways. Univariate and multivariate Cox regression analyses were applied to evaluate independent prognostic factors. Besides, associations between CACNA1C and immunity were also explored. Results CACNA1C had a lower expression in OC tumor tissues than in normal tissues (P < 0.001), with significant OS (P = 0.013) and a low diagnostic efficiency. We further validated the expression levels of CACNA1C in OC by means of the ICGC dataset (P = 0.01), qRT-PCR results (P < 0.001) and the HPA database. Univariate and multivariate Cox hazard regression analyses indicated that CACNA1C could be an independent risk factor of OS for OC patients (both P < 0.001). Five significant CACNA1C-related signaling pathways were identified by means of GSEA. As for genetic alteration analysis, altered CACNA1C groups were significantly associated with OS (P = 0.0169), progression-free survival (P = 0.0404), disease-free survival (P = 0.0417) and disease-specific survival (P = 9.280e-3), compared with unaltered groups in OC. Besides, CACNA1C was dramatically associated with microsatellite instability (MSI) and immunity. Conclusions Our results shed light on that CACNA1C could be a prognostic predictor of OS in OC and it was closely related to immunity.

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Identification and Validation of a PPP1R12A-Related Five-Gene Signature Associated With Metabolism to Predict the Prognosis of Patients With Prostate Cancer

Frontiers in Genetics ◽

10.3389/fgene.2021.703210 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhihao Zou ◽

Ren Liu ◽

Yingke Liang ◽

Rui Zhou ◽

Qishan Dai ◽

...

Keyword(s):

Prostate Cancer ◽

Cox Regression ◽

Expression Profiles ◽

Affinity Purification ◽

Disease Free Survival ◽

Gene Signature ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Free Survival ◽

Cox Regression Analysis

BackgroundProstate cancer (PCa) is the most common malignant male neoplasm in the American male population. Our prior studies have demonstrated that protein phosphatase 1 regulatory subunit 12A (PPP1R12A) could be an efficient prognostic factor in patients with PCa, promoting further investigation. The present study attempted to construct a gene signature based on PPP1R12A and metabolism-related genes to predict the prognosis of PCa patients.MethodsThe mRNA expression profiles of 499 tumor and 52 normal tissues were extracted from The Cancer Genome Atlas (TCGA) database. We selected differentially expressed PPP1R12A-related genes among these mRNAs. Tandem affinity purification-mass spectrometry was used to identify the proteins that directly interact with PPP1R12A. Gene set enrichment analysis (GSEA) was used to extract metabolism-related genes. Univariate Cox regression analysis and a random survival forest algorithm were used to confirm optimal genes to build a prognostic risk model.ResultsWe identified a five-gene signature (PPP1R12A, PTGS2, GGCT, AOX1, and NT5E) that was associated with PPP1R12A and metabolism in PCa, which effectively predicted disease-free survival (DFS) and biochemical relapse-free survival (BRFS). Moreover, the signature was validated by two internal datasets from TCGA and one external dataset from the Gene Expression Omnibus (GEO).ConclusionThe five-gene signature is an effective potential factor to predict the prognosis of PCa, classifying PCa patients into high- and low-risk groups, which might provide potential novel treatment strategies for these patients.

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TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

Cell Death and Disease ◽

10.1038/s41419-021-03734-4 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Sha Zhou ◽

Jianhong Peng ◽

Liuniu Xiao ◽

Caixia Zhou ◽

Yujing Fang ◽

...

Keyword(s):

Colorectal Cancer ◽

Disease Free Survival ◽

Free Survival ◽

Epigenetic Regulator ◽

Crc Management ◽

Disease Free ◽

Resistance To Chemotherapy

AbstractResistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.

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Identification of a lncRNA prognostic signature-related to stem cell index and its significance in colorectal cancer

Future Oncology ◽

10.2217/fon-2020-1163 ◽

2021 ◽

Author(s):

Xiao-Cheng Wang ◽

Ya Liu ◽

Fei-Wu Long ◽

Liang-Ren Liu ◽

Chuan-Wen Fan

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Prognostic Markers ◽

The Cancer Genome Atlas ◽

Prognostic Signature ◽

Free Survival ◽

Cancer Genome Atlas ◽

Bioinformatic Approaches ◽

Cell Phenotypes ◽

The Relationship

Background: The relationship between long noncoding RNAs (lncRNAs) and the mRNA stemness index (mRNAsi) in colorectal cancer (CRC) is still unclear. Materials & methods: The mRNAsi, mRNAsi-related lncRNAs and their clinical significance were analyzed by bioinformatic approaches in The Cancer Genome Atlas (TCGA)-COREAD dataset. Results: mRNAsi was negatively related to pathological features but positively related to overall survival and recurrence-free survival in CRC. A five mRNAsi-related lncRNAs prognostic signature was further developed and showed independent prognostic factors related to overall survival in CRC patients, due to the five mRNAsi-related lncRNAs involved in several pathways of the cancer stem cells and malignant cancer cell phenotypes. Conclusion: The present study highlights the potential roles of mRNAsi-related lncRNAs as alternative prognostic markers.

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A Comparative Study of Epidemiology, Clinicopathologic Features and Outcome of Colorectal Cancer Patients between Ain Shams University Hospitals and Luxor International Hospital

QJM ◽

10.1093/qjmed/hcab103.005 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Tarek Hussein Kamel ◽

Amr Lotfy Farag ◽

Dr/Sherif Hassanin Ahmed ◽

Chresteen Talaat Samy Hanna

Keyword(s):

Colorectal Cancer ◽

Comparative Study ◽

Disease Free Survival ◽

University Hospital ◽

Treatment Modalities ◽

Clinicopathologic Features ◽

Free Survival ◽

Significant Difference ◽

Group A ◽

Group B

Abstract Background Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is the third most common malignancy after lung & breast and the fourth leading cause of cancer-related deaths worldwide, accounting for approximately 1,400,000 new cases and about 700,000 deaths worldwide. Objectives The aim of this retrospective study is to compare the epidemiology, clinicopathologic features, different treatment modalities and outcomes regarding disease free survival (DFS), progression free survival (PFS) & overall survival (OS) of colorectal cancer disease between cases presented to Ain shams university hospital & to Luxor international hospital in 3 consecutive years. Patients and Methods The study is retrospective comparative study. Clinical oncology department in Ain Shams University Hospital and Luxor International Hospital. The data Collected from January 2013 to December 2015. This study analyzed hospital records of patients who diagnosed with colorectal cancer (CRC) and allocated into two groups: Group A: CRC patients presented to Ain-Shams University Hospital from January 2013 to December 2015, group B: CRC patients presented to Luxor International Hospital from January 2013 to December 2015. Results There was no statistically significant difference regarding age parameter in LIH when compared to ASU, but the study was consistent with higher incidence in patients who were aged more than forty- accounted about 70.5% in all CRC cases. Cases less than 40 years old, in group A were 35.2%, while in Group B were 23.5%. Even there was no statistically significant difference but it may be attributable to more westernization in Lower Egypt. Other explanation may be due to decreased low socioeconomic status and different lifestyle factors in more developing region what increase risk of colorectal cancer. Among our cases, there is no statistically significant difference regarding gender between the two hospitals. Both sexes almost were affected equally, females appeared to be at a slightly higher risk of developing CRC cancer with current prevalence 1.3:1 in ASU group, and 1.1:1 in LIH group. Conclusion The need to increase awareness about CRC in Egypt especially upper Egypt, is recommended. An awareness campaign should be performed to promote detection of CRC at its earliest and most curable stage by recognizing early symptoms and enabling early referrals for colonoscopy. Those at higher risk should be offered more intensive surveillance. Similarity of the data from different centers suggests that this is the picture of colorectal cancer typical of Egypt.

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