Systematic Analysis of the Oncogenic Role of WDR62 in Human Tumors

Background. Emerging studies support the oncogenic role of WD repeat domain 62 (WDR62) in few tumors, while no pan-cancer analysis is available. In this study, we analyzed systematically the oncogenic role of WDR62 across a series of human tumors based on bioinformatic data mining. Methods. The expression level of WDR62 was analyzed via GEPIA2, TIMER, UALCAN, and StarBase databases. The prognostic role was analyzed via GEPIA2, TIMER, UALCAN, StarBase, TISIDB, TCGA portal, Kaplan-Meier Plotter, and PrognoScan databases. Then, we explored the causes for WDR62 abnormal expression via TCGA portal and UALCAN databases. Subsequently, the STRING and GeneMANIA databases were used to find the interactive networks for WDR62. Furthermore, we analyzed the correlation between WDR62 expression and immune features via TIMER and TISIDB databases. Results. We found that WDR62 was significantly upregulated in most of the tumors and correlated with poor prognosis mainly in 6 candidate tumors—BLCA, BRCA, KIRC, KIRP, LIHC, and LUAD. Abnormal WDR62 expression may be probably attributed to TP53 mutation and promoter DNA methylation. Relative network analysis demonstrated that WDR62 was mainly involved in MAPK and toll-like receptor signaling pathway. WDR62 expression was associated with various immune cell infiltrations, especially cancer-associated fibroblasts (CAF) and T cell regulatory (Treg) cells, and was markedly correlated with poor prognosis. Moreover, WDR62 expression was closely associated with the expression of some immunomodulators such as PD-L1 and has a significant prognostic value. Conclusions. Our study revealed that WDR62 could serve as a diagnostic and prognostic biomarker for several cancers. Importantly, WDR62 was closely associated with various immune cell infiltration, and to a certain extent, it can predict the effect of immunotherapy in particular PD1/PD-L1 inhibitors. Our pan-cancer study provided useful information on the oncogenic role of WDR62, contributing to further exploring the underlying mechanisms.

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KMT2C as a positive predictor for treatment of immune checkpoint inhibitor and correlation with immune infiltrates in colorectal cancer (CRC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3538 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3538-3538

Author(s):

Ling Zhang ◽

Jianping Song ◽

Yiting Wang ◽

Yaoxu Chen

Keyword(s):

Colorectal Cancer ◽

Survival Data ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Immune Cell ◽

Checkpoint Inhibitor ◽

Colon Adenocarcinoma ◽

Treg Cells ◽

Prognostic Effect

3538 Background: Lysine Methyltransferase 2C (KMT2C), a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family, possesses histone methylation activity and is involved in transcriptional co-activation. Present study has shown that KMT2C is positive correlated with better efficacy of Immune checkpoint inhibitor (ICI) in NSCLC. However, the role of KMT2C in treatment of ICI on colorectal cancer (CRC) is still unknown. Methods: NGS (Next Generation Sequencing) was performed on 1628 CRC patients. TMB of these patients were analyzed. A public accessible cohort (Samstein2018) with data from 130 CRC patients were used to investigate the correlation between KMT2C mutation and efficacy of ICI. WES and survival data of TCGA database (1099 CRC) was used to analyze prognostic effect of KMT2C mutation. Furthermore, CIBERSORT was used to analyze the tumor-infiltrating immune cells present in COAD（colon adenocarcinoma, 404 patients）from TCGA database. Results: Among 1628 CRC patient, 230(14.1%) had KMT2C mutation. TMB was positive correlated with KMT2C mutation (Mut vs. WT, 30.75 vs. 7.26 mut/Mb, p < 0.0001). The Samstein2018 cohort showed that KMT2C mutations (15.4%, 20/130) were significantly associated with better OS (Mut vs. WT, 11.5 vs. 7.5 month, HR = 0.29; 95% CI, 0.1-0.81; P = 0.012), and a higher TMB was also observed in KMT2C-Mut group (p = 1.98e-08). In TCGA, no association between KMT2C mutation and OS was observed (P = 0.23), suggesting that was not prognostic factor. Moreover, we analyzed the relationship between KMT2C mutation and immune cell infiltration through CRC TCGA database. The results showed, in COAD, KMT2C mutation was positively correlated with the abundance of CD8+ T cells (P = 0.0014), B cells (P = 0.014), M1 macrophages (P = 0.015), neutrophil (P = 0.0019) and NK cells (P = 0.043), and negatively correlated with Treg cells (p = 0.0063). Conclusions: KMT2C has an impact on the immune microenvironment and may be used as a potential positive predictor for treatment of ICI on CRC patients. The role of KMT2C in immunotherapy warrant further studies.

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Tumor infiltrating immune cells (TIICs) as a biomarker for prognosis benefits in patients with osteosarcoma

BMC Cancer ◽

10.1186/s12885-020-07536-3 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Ying Chen ◽

Bo Zhao ◽

Xiaohu Wang

Keyword(s):

Risk Score ◽

Immune Cells ◽

Poor Prognosis ◽

Immune Cell ◽

Cell Types ◽

Difficult Problem ◽

Model Base ◽

Model Based ◽

Kaplan Meier ◽

Score Model

Abstract Background Osteosarcoma is a rare malignant bone tumor in adolescents and children. Poor prognosis has always been a difficult problem for patients with osteosarcoma. Recent studies have shown that tumor infiltrating immune cells (TIICs) are associated with the clinical outcome of osteosarcoma patients. The aim of our research was to construct a risk score model based on TIICs to predict the prognosis of patients with osteosarcoma. Methods CIBERSORTX algorithm was used to calculate the proportion of 22 TIIC types in osteosarcoma samples. Kaplan-Meier curves were drawn to investigate the prognostic value of 22 TIIC types. Forward stepwise approach was used to screen a minimal set of immune cell types. Multivariate Cox PHR analysis was performed to construct an immune risk score model. Results Osteosarcoma samples with CIBERSORTX output p value less than 0.05 were selected for research. Kaplan-Meier curves indicated that naive B cells (p = 0.047) and Monocytes (p = 0.03) in osteosarcoma are associated with poor prognosis. An immune risk score model was constructed base on eight immune cell types, and the ROC curve showed that the immune risk score model is reliable in predicting the prognosis of patients with osteosarcoma (AUC = 0.724). Besides, a nomogram model base on eight immune cell types was constructed to predict the survival rate of patients with osteosarcoma. Conclusions TIICs are closely related to the prognosis of osteosarcoma. The immune risk score model based on TIICs is reliable in predicting the prognosis of osteosarcoma.

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Hypermethylation of MT1G and MT1H CpGs Promoter Sites and High Serum Levels of Cu Affect Survival Rate of Patients Affected by Hepatocellular Carcinoma

Current Developments in Nutrition ◽

10.1093/cdn/nzaa067_018 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1791-1791

Author(s):

Domenica De Santis ◽

Silvia Udali ◽

Andrea Ruzzenente ◽

Greta Beschin ◽

Patrizia Pattini ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Methylation ◽

Trace Elements ◽

Survival Rate ◽

Mortality Rate ◽

Liver Tissue ◽

Kaplan Meier ◽

Promoter Dna Methylation ◽

Promoter Dna

Abstract Objectives Recent evidences suggest a principal role of trace elements and metallothioneins (MTs), proteins involved in metal ions homeostasis and detoxification, in hepatocellular carcinogenesis. The study was designed to evaluate whether serum and liver tissue concentrations of the trace elements Cu, Zn and Se are implicated in survival rate of hepatocellular carcinoma (HCC) patients and if promoter DNA methylation is involved in trace elements-related proteins regulation. Methods Cu, Zn and Se levels were determined in serum and liver tissue samples, both HCC and homologous non neoplastic tissue (N) of 27 HCC patients by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Gene expression analysis of MT1G and MT1H, was performed by Real-time qPCR in HCC and N tissue. Promoter DNA methylation of a region overlapping MT1G and MT1H promoters was assessed by bisulfite amplicon sequencing (BSAS) in HCC and N tissues of 23 patients. Kaplan-Meier survival curves were drawn using the log-rank test (Mantel-Cox test) to examine the differences in survival according to serum trace elements and to gene-specific methylation levels. Results Kaplan-Meier analysis according to serum Cu levels showed that subjects within the highest quintile had an increased mortality rate (88.9%) compared with the other four quintiles (P = 0.025). Considering the 80th percentile of Cu levels (1118 μg/L), subjects with Cu concentrations above this value had a significantly decreased survival rate (P < 0.001). Se and Zn content were depleted in HCC tissues as compared to N tissues (P < 0.0001). MT1G and MT1H were strongly repressed in HCC tissues and precisely, MT1H in 24 out of 27 HCC tissues (P = 0.008) and MT1G in 23 out of 27 HCC tissues (P = 0.037). Nine out of 19 HCC tissues showing a down-regulation of MTs with three CpG sites, significantly hypermethylated in HCC tissue as compared to N tissue (P < 0.05). Considering the median methylation level, patients with higher methylation values showed increased mortality rate (P = 0.015). Conclusions The significant repression of MT1G and MT1H in HCC tissue is related to promoter hypermethylation and support the hypothesis of MT1G and MT1H as possible tumor suppressor genes in HCC. The evidence of promoter methylation levels and survival rate association provide new insights for the role of DNA methylation in liver carcinogenesis. Funding Sources N/A.

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Pan-cancer analysis of the oncogenic role of discs large homolog associated protein 5 (DLGAP5) in human tumors

Cancer Cell International ◽

10.1186/s12935-021-02155-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Neng Tang ◽

Xiaolin Dou ◽

Xing You ◽

Qiman Shi ◽

Mujing Ke ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Carcinoma ◽

Cell Lines ◽

Cellular Proliferation ◽

Germ Cell Tumors ◽

Enrichment Analysis ◽

Human Tumors ◽

Testicular Germ Cell ◽

Pan Cancer

Abstract Background In recent years, there have been many studies on the relationship between DLGAP5 and different types of cancers, yet there is no pan-cancer analysis of DLGAP5. Therefore, this study aims to analyze the roles of DLGAP5 in human tumors. Methods Firstly, we evaluated the expression level of DLGAP5 in 33 types of tumors throughout the datasets of TCGA (Cancer Genome Atlas) and GEO (Gene Expression Synthesis). Secondly, we used the GEPIA2 and Kaplan-Meier plotter to conduct Survival prognosis analysis. Additionally, cBioPortal web was utilized to analyze the genetic alteration of DLGAP5, after which we selected hepatocellular carcinoma (HCC) cell lines to define the function of DLGAP5. Last but not least, we performed immune infiltration analysis and DLGAP5-related gene enrichment analysis. Results DLGAP5 is highly expressed in most type of cancers, and there is a significant correlation between the expression of DLGAP5 and the prognosis of cancer patients. We have observed that DLGAP5 promotes the proliferation and invasion of hepatocellular carcinoma (HCC) cell lines. We also found that DLGAP5 expression was related with the CD8+ T-cell infiltration status in kidney renal clear cell carcinoma, uveal melanoma, and thymoma, and cancer-associated fibroblast infiltration was observed in breast invasive carcinoma, kidney renal papillary cell carcinoma and testicular germ cell tumors. In addition, enrichment analysis revealed that cell cycle- and oocyte meiosis-associated functions were involved in the functional mechanism of DLGAP5. Conclusions Taken together, our unpresented pan-cancer analysis of DLGAP5 provides a relatively integrative understanding of the oncogenic role of DLGAP5 in various tumors. DLGAP5 may prompt HCC cellular proliferation, invasion and metastasis. All of these provides solid basement and will promote more advanced understanding the role of DLGAP5 in tumorigenesis and development from the perspective of clinical tumor samples and cells.

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UPF1 Promotes Chemoresistance to Oxaliplatin Through Maintenance of Stemness by Increasing Phosphorylated TOP2A in Colorectal Cancer.

10.21203/rs.3.rs-130880/v1 ◽

2020 ◽

Author(s):

Congcong Zhu ◽

Long Zhang ◽

Senlin Zhao ◽

Weixing Dai ◽

Yun Xu ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Cell Lines ◽

Clinical Relevance ◽

Poor Prognosis ◽

Therapy Strategy ◽

Underlying Mechanisms

Abstract Background: UPF1 is proved to dysregulate in multiple tumors and influence carcinogenesis. However, the role of UPF1 on oxaliplatin resistance in colorectal cancer (CRC) remains unknown.Methods: Firstly, we investigated the clinical relevance of UPF1 in CRC patients. Then, we explored the influence of UPF1 on chemoresistance to oxaliplatin in vitro and in vivo. Finally, we disclosed the underlying mechanisms of oxaliplatin resistance induced by UPF1.Results: UPF1 is upregulated in CRC and overexpression of UPF1 more likely results in recurrence in CRC patients and predicts a poorer overall survival (OS). UPF1 maintains stemness in CRC cell lines and promotes chemoresistance to oxaliplatin in CRC. UPF1-induced oxaliplatin resistance can be associated with interaction with TOP2A and increasing phosphorylated TOP2A.Conclusions: UPF1 was overexpressed and predicted a poor prognosis in CRC. UPF1 enhanced the stemness and chemoresistance to oxaliplatin by interaction with TOP2A and increase of phosphorylated TOP2A in CRC, which may provide a new therapy strategy for chemoresistance to oxaliplatin in CRC patients.

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Upregulated CCNE1 Correlates with Poor Prognosis, Tumor Immune Infiltration and Escape in Breast Cancer

10.21203/rs.3.rs-966772/v1 ◽

2021 ◽

Author(s):

Jiaxi Feng ◽

Yanan Hu ◽

Dan Liu ◽

Shanshan Wang ◽

Mengci Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Immune Cells ◽

Poor Prognosis ◽

Immune Cell ◽

High Expression ◽

Expression Level ◽

Immune Cell Infiltration ◽

Immune Infiltration ◽

Kaplan Meier ◽

Kaplan Meier Plotter

Abstract Background Breast cancer (BC) is the most common malignant tumor in women and widely known for its poor prognosis. More and more research has discovered that cyclin E1 (CCNE1) plays an important role in progression of various types of cancer. But its specific mechanism in BC progression still needs further research to explore.Methods At first, we determined the expression and prognostic value of CCNE1 through The Cancer Genome Atlas (TCGA) database and The Genotype-Tissue Expression (GTEx) data. Then, we predicted the upstream non-coding RNAs of CCNE1 through StarBase, GEPIA, and Kaplan-Meier plotter database. We further studied the correlation of CCNE1 expression with BC immune cell infiltration, biomarkers of immune cells and immune checkpoints expression through TIMER and GEPIA databases.Results The results suggested that CCNE1 was significantly upregulated in BC and its high expression was correlated with poor prognosis in BC patients. Next, we identified long noncoding RNA (lncRNA) LINC00511 / microRNA-195-5p (miR-195-5p) / CCNE1 axis as the most potential pathway that could regulate CCNE1 expression in BC through StarBase, GEPIA, and Kaplan-Meier plotter database. Furthermore, our in-depth research discovered that CCNE1 expression level was significantly correlated with tumor immune cell inﬁltration, biomarkers of immune cells, and immune checkpoint expression in BC. conclusions In summary, high expression level of CCNE1 was significantly correlated with poor prognosis, tumor immune infiltration and escape in BC.

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Increased IGFBP7 Expression Correlates with Poor Prognosis and Immune Infiltration in Gastric Cancer: An Integrated Bioinformatics Analysis

10.21203/rs.3.rs-33369/v1 ◽

2020 ◽

Author(s):

Qiaoyun Zhao ◽

Rulin Zhao ◽

Conghua Song ◽

Huan Wang ◽

Jianfang Rong ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Poor Prognosis ◽

Bioinformatics Analysis ◽

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Biological Processes ◽

Coexpressed Genes

Abstract Background Insulin-like growth factor binding protein-7 (IGFBP7) contributes to multiple biological processes in various tumors. However, the role of IGFBP7 in gastric cancer (GC) is still undetermined. The study aims to explore the role of IGFBP7 in GC via an integrated bioinformatics analysis.Methods IGFBP7 expression levels in GC and its normal gastric tissues were analyzed using multiple databases, including the Tumor Immune Estimation Resource (TIMER), Oncomine, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The methylation analysis was conducted with MEXPRESS, UALCAN and Xena online tools. The survival analysis was conducted using the Kaplan-Meier Plotter and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Coexpressed genes of IGFBP7 were selected with the cBioPortal tool and enrichment analysis was conducted with the clusterProfiler package in R software. Gene set enrichment analysis (GSEA) was performed to explore the IGFBP7-related biological processes involved in GC. Correlations between IGFBP7 and immune cell infiltrates were analyzed using the TIMER database.Results IGFBP7 expression was significantly upregulated in GC and correlated with stage, grade, tumor status and Helicobacter pylori infection. High IGFBP7 expression and low IGFBP7 methylation levels were significantly associated with short survival of patients with GC. Univariate and multivariate analyses revealed that IGFBP7 was an independent risk factor for GC. The coexpressed genes LHFPL6, SEPTIN4, HSPB2, LAYN and GGT5 predicted unfavorable outcomes of GC. Enrichment analysis showed that the coexpressed genes were involved in extracellular matrix (ECM)-related processes. GSEA indicated that IGFBP7 was positively related to ECM and inflammation-related pathways. TIMER analysis indicated that the IGFBP7 expression level was strongly correlated with genes related to various infiltrating immune cells in GC, especially with gene markers of tumor associated macrophages (TAMs).Conclusions We demonstrate that increased IGFBP7 expression correlates with poor prognosis and immune cell infiltration in GC. IGFBP7 might be a potential biomarker for the diagnosis and targeted therapy for GC.

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Identification of SHMT2 as a Potential Prognostic Biomarker and Correlating With Immune Infiltrates in Lung Adenocarcinoma

10.21203/rs.3.rs-105348/v1 ◽

2020 ◽

Author(s):

Lianxiang Luo ◽

Yushi Zheng ◽

Zhiping Lin ◽

Xiaodi Li ◽

Xiaoling Li ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Immune Cell ◽

Prognostic Biomarker ◽

Tumor Infiltrating Lymphocytes ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Kaplan Meier ◽

Online Databases ◽

Cox Proportional Hazard Regression

Abstract Background: The role of Serine hydroxymethyltransferase2 (SHMT2) in diverse cancers has attracted increasing attention. However, the prognostic role of SHMT2 in lung adenocarcinoma (LUAD) and its relationship with immune cell infiltration is yet to be studied.Methods: The data of mRNA and clinic in LUAD were respectively downloaded from the GEO and TCGA database. We conducted a biological analysis to select the signature gene SHMT2. Online databases including Oncomine, GEPIA, TISIDB, TIMER, and HPA were applied to analyze the characterization of SHMT2 expression, prognosis and the correlation with immune infiltrates in LUAD.Results: The mRNA expression and protein expression of SHMT2 in LUAD were higher than normal tissue. A Kaplan-Meier analysis showed the lower expression level of SHMT2 had a better overall survival rate. Multivariate analysis and the Cox proportional hazard regression model revealed that SHMT2 expression was an independent prognostic factor for patients with LUAD. Meanwhile, the gene SHMT2 was highly associated with tumor-infiltrating lymphocytes in LUAD.Conclusions: These results suggest that the SHMT2 gene is a promising candidate as a potential prognostic biomarker and highly associated with different types of phenotypes of immune cell infiltration in LUAD.

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Bromine domain protein 4 is an important marker for prognosis of ovarian cancer and tumor immune infiltration

10.21203/rs.3.rs-270956/v1 ◽

2021 ◽

Author(s):

Chujia Chen ◽

Zhiyong Yang ◽

Qiuchan Zhao ◽

Bangming Xu ◽

Donglin Cao

Keyword(s):

Ovarian Cancer ◽

Immune Cell ◽

Expression Level ◽

Immune Markers ◽

Immune Infiltration ◽

Normal Tissues ◽

Kaplan Meier ◽

Domain Protein ◽

Kaplan Meier Plotter

Abstract Background Ovarian cancer (OC) is one of the most common malignant gynecological tumors, but its pathogenesis is unclear. Bromine domain protein 4 (BRD4) is involved in the malignant transformation of cells, as well as the invasion and metastasis of tumor cells. The biological role of BRD4 in ovarian cancer is yet to be determined. Methods The differential expression of BRD4 in OC and corresponding normal tissues was evaluated by exploring the Tumor Immune Assessment Resources (TIMER) and the Oncomine database. The correlation between the expression level of BRD4 and the prognosis of OC patients was evaluated using the Kaplan-Meier Plotter database. Using TIMER, we further studied the correlation between BRD4 and tumor immune cell infiltration. Results The expression of BRD4 was significantly higher in patients with OC, and high BRD4 expression was closely related to low overall survival rate. The BRD4 expression was associated with the levels of immune markers of macrophages, dendritic cells, neutrophils, and various effector T cells. Taken together, these findings show that BRD4 expression is significantly related to immune infiltration in OC and suggest that BRD4 might play an important role in the immune evasion of OC cells. Conclusion The expression level of BRD4 in OC tissues is significantly upregulated, and its high expression is significantly associated with poor prognosis of patients and is closely related to tumor immune infiltration. These results suggest that BRD4 can be used as a prognostic marker and a marker of immune infiltration in OC.

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A Multilevel Systemic Pan-cancer Analysis: Collagen Triple Helix Repeat Containing-1 is a Potential Target for Tumor Immunotherapy

10.21203/rs.3.rs-1016486/v1 ◽

2021 ◽

Author(s):

Jiangtao Zhang ◽

Xianghua Wu ◽

Huichao Ruan ◽

Changli Wang ◽

Rong qiang Yang ◽

...

Keyword(s):

Immune Cell ◽

Tumor Immunotherapy ◽

Genomic Changes ◽

Collagen Triple Helix ◽

Kaplan Meier ◽

Tumor Tissues ◽

Bioinformatics Databases ◽

Cell Components ◽

Cancer Tissues ◽

Pan Cancer

Abstract Background: Cancer is one of the leading causes of pathological death in humans. Although CTHRC1 is a prooncogene highly expressed in a variety of tumor tissues, the specific biological mechanisms of CTHRC1 involvement in cancer development need to be elucidated. Methods: In the present study, nine online bioinformatics databases were employed to explore the potential prognostic and grading value of CTHRC1 in generalized cancer as well as its potential role in regulating tumor immunity. Results: Data from GEPIA2.0, Oncomine, TNMplot, Kaplan-Meier Plotter and TISIDB database had consistently demonstrated that CTHRC1 was associated with the expression, prognosis and typing in most cancer tissues. Cbioportal and SMART analysis revealed that genomic changes and methylation of CTHRC1 in most tumor tissues. Finally, Sangerbox and TIMER database analysis suggested that CTHRC1 was involved in the changes of immune cell components in tumor immune microenvironment, with certain heterogeneity. Meanwhile, CTHRC1 was correlated with TMB, MSI, neoantigen and tumor immune checkpoint, especially CD276. Conclusion: CTHRC1 had the potential as a prognostic and grading molecular marker for pan-cancer. And CTHRC1-related targeting agents may be a novel breakthrough in tumor immunotherapy.

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