Through The Cancer Genome Atlas Research Articles

THAP3 recruits SMYD3 to OXPHOS genes and epigenetically promotes mitochondrial respiration in hepatocellular carcinoma.

Mitochondria harbor the oxidative phosphorylation (OXPHOS) system to sustain cellular respiration. However, the transcriptional regulation of OXPHOS remains largely unexplored. Through the cancer genome atlas (TCGA) transcriptome analysis, transcription factor THAP domain-containing 3 (THAP3) was found to be strongly associated with OXPHOS gene expression. Mechanistically, THAP3 recruited the histone methyltransferase SET and MYND domain-containing protein 3 (SMYD3) to upregulate H3K4me3 and promote OXPHOS gene expression. The levels of THAP3 and SMYD3 were altered by metabolic cues. They collaboratively supported liver cancer cell proliferation and colony formation. In clinical human liver cancer, both of them were overexpressed. THAP3 positively correlated with OXPHOS gene expression. Together, THAP3 cooperates with SMYD3 to epigenetically upregulate cellular respiration and liver cancer cell proliferation.

A novel anoikis-related gene signature can predict the prognosis of hepatocarcinoma patients.

Hepatocellular carcinoma (HCC) is a major health problem with more than 850,000 cases per year worldwide. This cancer is now the third leading cause of cancer-related deaths worldwide, and the number is rising. Cancer cells develop anoikis resistance which is a vital step during cancer progression and metastatic colonization. However, there is not much research that specifically addresses the role of anoikis in HCC, especially in terms of prognosis. This study obtained gene expression data and clinical information from 371 HCC patients through The Cancer Genome Atlas (TCGA) Program and The Gene Expression Omnibus (GEO) databases. A total of 516 anoikis-related genes (ANRGs) were retrieved from GeneCard database and Harmonizome portal. Differential expression analysis identified 219 differentially expressed genes (DEGs), and univariate Cox regression analysis was utilized to select 99 ANRGs associated with the prognosis of HCC patients. A risk scoring model with seven genes was established using the least absolute shrinkage and selection operator (LASSO) regression model, and internal validation of the model was performed. The identified 99 ANRGs are closely associated with the prognosis of HCC patients. The risk scoring model based on seven characteristic genes demonstrates excellent predictive performance, further validated by receiver operating characteristic (ROC) curves and Kaplan-Meier survival curves. The study reveals significant differences in immune cell infiltration, gene expression, and survival status among different risk groups. The prognosis of HCC patients can be predicted using a unique prognostic model built on ANRGs in HCC.

Expression of FAT1 in Lung Adenocarcinoma and Its Relationship with Immune Cell Infiltration

Lung cancer is a leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) is the most common pathological subtype, with adenocarcinoma being the predominant type. FAT atypical cadherin 1 (FAT1) is a receptor-like protein with a high frequency of mutations in lung adenocarcinoma. The protein encoded by FAT1 plays a crucial role in processes such as cell adhesion, proliferation, and differentiation. This study aims to investigate the expression of FAT1 in lung adenocarcinoma and its relationship with immune infiltration. Gene expression levels and relevant clinical information of 513 lung adenocarcinoma samples and 397 adjacent lung samples were obtained through The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data. The mRNA expression levels of the FAT1 gene in lung adenocarcinoma tissues were analyzed, along with its association with the prognosis of lung adenocarcinoma patients. Pathway enrichment analysis was conducted to explore the signaling pathways regulated by the FAT1 gene. Immunoblotting was used to detect the differential expression of FAT1 in lung epithelial cells and various lung cancer cell lines, while immunohistochemistry was employed to assess FAT1 expression in lung cancer and adjacent tissues. FAT1 gene mutations were identified in 14% of lung adenocarcinoma patients. TCGA database data revealed significantly higher FAT1 mRNA expression in lung adenocarcinoma tissues compared to adjacent lung tissues. Kaplan-Meier analysis indicated lower survival rates in lung adenocarcinoma patients with higher FAT gene expression. Pathway enrichment analysis suggested the involvement of FAT1 in tumor development pathways, and its expression was closely associated with immune cell infiltration. Immunohistochemical validation demonstrated significantly higher expression of FAT1 in cancer tissues compared to adjacent lung tissues. FAT1 mRNA is highly expressed in lung adenocarcinoma tissues, and elevated FAT1 mRNA expression is associated with poor prognosis in lung adenocarcinoma patients. FAT1 may serve as a potential biomarker for lung cancer.

CCDC71L as a novel prognostic marker and immunotherapy target via lipid metabolism in head and neck squamous cell carcinoma

BackgroundHead and neck squamous cell carcinoma (HNSCC) is the sixth most widespread cancer globally with high rate and poor prognosis. Coiled-coil domain containing 71 like (CCDC71L) exerts an important role in cellular lipid metabolic process. However, its function in HNSCC remains unclear. To this end, we examined the CCDC71L implications for prognosis and tumor microenvironment in HNSCC. Materials and methodsFirst, CCDC71L expression was explored through The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), the Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Gene Expression Omnibus (GEO) databases. The clinicpathological information were obtained from the dataset of TCGA. The Kaplan–Meier Plotter databases and Cox model were performed for the determination of prognostic values of CCDC71L, including the overall survival (OS), progress free interval (PFI), recurrence-free survival (RFS) and disease specific survival (DSS). Then, the potential mechanism of CCDC71L in HNSCC development was elucidated by means of Gene set enrichment analysis (GSEA) and Metascape databases. Furthermore, the relevance of CCDC71L to immune cells infiltration and immune checkpoints was assessed. The correlations among CCDC71L expression, mutational landscape and genome heterogeneity [mutant-allele tumor heterogeneity (MATH) and tumor purity] were detected by the data in TCGA. ResultsCCDC71L expression was significantly upregulated in HNSCC, and positively associated with age, gender and N stage. Higher CCDC71L expression resulted in poor OS, RFS, DSS and PFI. Multivariate Cox regression analysis showed CCDC71L would be an independent prognostic marker in patients with HNSCC. Moreover, CCDC71L and the level of macrophage and neutrophil cells infiltration were significantly correlated in HNSCC. High expression of CCDC71L was related to immune checkpoint genes, oncogene mutations and genome heterogeneity markers. ConclusionThese results implied that CCDC71L plays vital roles in HNSCC progression, which could be used as a underlying biomarker for the diagnosis and prognosis of HNSCC. Meanwhile, CCDC71L participates in immune regulation, which has a potential value for the immunotherapy of HNSCC patients.

Spindle and kinetochore-related complex subunit 3 has a protumour function in osteosarcoma by activating the Notch pathway

Increasing expression of spindle and kinetochore-related complex subunit 3 (SKA3) is related to the progression of multiple malignancies. However, the role of SKA3 in osteosarcoma remains unexplored. The present study aimed to investigate the relevance of SKA3 in osteosarcoma. Preliminarily, SKA3 expression in osteosarcoma was assessed through The Cancer Genome Atlas (TCGA) analysis, which revealed high levels of SKA3 transcripts in osteosarcoma tissues. Subsequent examination of clinical tissues confirmed the abundant expression of SKA3 in osteosarcoma. Downregulation of SKA3 expression in osteosarcoma cell lines resulted in repressive effects on cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT), while upregulation of SKA3 expression had the opposite effect. Gene set enrichment analysis (GSEA) revealed that the Notch pathway is enriched in SKA3 high groups based on different expressed genes from the TCGA data. Further investigation showed that the levels of Notch1, Notch1 intracellular domain (NICD1), hairy and enhancer of split 1 (HES1), and hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) were downregulated in SKA3-silenced osteosarcoma cells, and upregulated in SKA3-overexpressed osteosarcoma cells. Activation of the Notch pathway by increasing NICD1 expression reversed the antitumour effects induced by SKA3 silencing, while deactivation of the Notch pathway diminished the protumour effects induced by SKA3 overexpression. Moreover, SKA3-silenced osteosarcoma cells exhibited a reduced capacity for xenograft formation in nude mice. In conclusion, SKA3 plays a cancer-enhancing role in osteosarcoma through its effect on the Notch pathway. Reducing the expression of SKA3 could be a potential therapeutic approach for treating osteosarcoma.

Identification and validation of novel prognostic fatty acid metabolic gene signatures in colon adenocarcinoma through systematic approaches.

Colorectal cancer (CRC) belongs to the class of significantly malignant tumors found in humans. Recently, dysregulated fatty acid metabolism (FAM) has been a topic of attention due to its modulation in cancer, specifically CRC. However, the regulatory FAM pathways in CRC require comprehensive elucidation. The clinical and gene expression data of 175 fatty acid metabolic genes (FAMGs) linked with colon adenocarcinoma (COAD) and normal cornerstone genes were gathered through The Cancer Genome Atlas (TCGA)-COAD corroborating with the Molecular Signature Database v7.2 (MSigDB). Initially, crucial prognostic genes were selected by uni- and multi-variate Cox proportional regression analyses; then, depending upon these identified signature genes and clinical variables, a nomogram was generated. Lastly, to assess tumor immune characteristics, concomitant evaluation of tumor immune evasion/risk scoring were elucidated. A 8-gene signature, including ACBD4, ACOX1, CD36, CPT2, ELOVL3, ELOVL6, ENO3, and SUCLG2, was generated, and depending upon this, CRC patients were categorized within high-risk (H-R) and low-risk (L-R) cohorts. Furthermore, risk and age-based nomograms indicated moderate discrimination and good calibration. The data confirmed that the 8-gene model efficiently predicted CRC patients' prognosis. Moreover, according to the conjoint analysis of tumor immune evasion and the risk scorings, the H-R cohort had an immunosuppressive tumor microenvironment, which caused a substandard prognosis. This investigation established a FAMGs-based prognostic model with substantially high predictive value, providing the possibility for improved individualized treatment for CRC individuals.

NCDN is a Potential Biomarker and Therapeutic Target for Glioblastoma.

Background: Glioblastoma (GBM) is a type of central nervous system malignancy. In our study, we determined the effect of NCDN in GBM patients through The Cancer Genome Atlas (TCGA) data analysis, and studied the effects of NCDN on GBM cell function to estimate its potential as a therapeutic target. Methods: Gene expression profiles of glioblastoma cohort were acquired from TCGA database and analyzed to look for central genes that may serve as GBM therapeutic targets. Then the cell function of NCDN in glioblastoma cell was explored through in vitro cell experiments. Results: Through gene ontology (GO) analysis, weighted gene co-expression network analysis (WGCNA), and survival analysis, we identified three key genes (NCDN, PAK1 and SPRYD3) associated with poor prognosis in glioblastoma. In vitro experiments showed impaired cell migration, apoptosis, and cell cycle arrest in NCDN knockdown cells. Conclusion: NCDN affects the progress and prognosis of glioblastoma by promoting cell migration and inhibiting apoptosis.

Comprehensive bioinformatics analysis of FXR1 across pan-cancer: Unraveling its diagnostic, prognostic, and immunological significance.

Fragile X-related protein 1 (FXR1) is an RNA-binding protein that belongs to the fragile X-related (FXR) family. Studies have shown that FXR1 plays an important role in cancer cell proliferation, invasion and migration and is differentially expressed in cancers. This study aimed to gain a comprehensive and systematic understanding of the analysis of FXR1's role in cancers. This would lead to a better understanding of how it contributes to the development and progression of various malignancies. this study conducted through The Cancer Genome Atlas (TCGA), GTEx, cBioPortal, TISIDB, GEPIA2 and HPA databases to investigated FXR1's role in cancers. For data analysis, various software platforms and web platforms were used, such as R, Cytoscape, hiplot plateform. A significant difference in FXR1 expression was observed across molecular and immune subtypes and across types of cancer. FXR1 expression correlates with disease-specific survival (DSS), and overall survival (OS) in several cancer pathways, further in progression-free interval (PFI) in most cancers. Additionally, FXR1 showed a correlation with genetic markers of immunomodulators in different cancer types. Our study provides insights into the role of FXR1 in promoting, inhibiting, and treating diverse cancers. FXR1 has the potential to serve as a diagnostic and prognostic biomarker for cancer, with therapeutic value in immune-based, targeted, or cytotoxic treatments. Further clinical validation and exploration of FXR1 in cancer treatment is necessary.

Expression and gene regulatory network of S100A16 protein in cervical cancer cells based on data mining

S100A16 protein belongs to the S100 family of calcium-binding proteins, which is widely distributed in human tissues and highly conserved. S100 calcium-binding proteins possess broad biological functions, such as cancer cell proliferation, apoptosis, tumor metastasis, and inflammation (Nat Rev Cancer 15:96–109, 2015). The S100A16 protein was initially isolated from a cell line derived from astrocytoma. The S100A16 protein, consisting of 103 amino acids, is a small acidic protein with a molecular weight of 11,801.4 Da and an isoelectric point (pI) of 6.28 (Biochem Biophys Res Commun 313:237–244, 2004). This protein exhibits high conservation among mammals and is widely expressed in various human tissues (Biochem Biophys Res Commun 322:1111–1122, 2004). Like other S100 proteins, S100A16 contains two EF-hand motifs that form a helix-loop-helix structural domain. The N-terminal domain and the C-terminal domain of S100A16 are connected by a "hinge" linker.S100A16 protein exhibits distinct characteristics that distinguish it from other S100 proteins. A notable feature is the presence of a single functional Ca2 + binding site located in the C-terminal EF-hand, consisting of 12 amino acids per protein monomer (J Biol Chem 281:38905–38917, 2006). In contrast, the N-terminal EF-hand of S100A16 comprises 15 amino acids instead of the typical 14, and it lacks the conserved glutamate residue at the final position. This unique attribute may contribute to the impaired Ca2 + binding capability in the N-terminal region (J Biol Chem 281:38905–38917, 2006). Studies have shown an integral role of S100 calcium-binding proteins in the diagnosis, treatment, and prognosis of certain diseases (Cancers 12:2037, 2020). Abnormal expression of S100A16 protein is implicated in the progression of breast and prostate cancer, but an inhibitor of oral cancer and acute lymphoblastic leukemia tumor cell proliferation (BMC Cancer 15:53, 2015; BMC Cancer 15:631, 2015). Tu et al. (Front Cell Dev Biol 9:645641, 2021) indicate that the overexpression of S100A16 mRNA in cervical cancer(CC) such as cervical squamous cell carcinoma and endocervical adenocarcinoma as compared to the control specimens. Tomiyama N. and co-workers (Oncol Lett 15:9929–9933, 2018) (Tomiyama, N) investigated the role of S100A16 in cancer stem cells using Yumoto cells (a CC cell line),The authors found upregulation of S100A16 in Yumoto cells following sphere formation as compared to monolayer culture.Despite a certain degree of understanding, the exact biological function of S100A16 in CC is still unclear. This article explores the role of S100A16 in CC through a bioinformatics analysis. Referencing the mRNA expression and SNP data of cervical cancer available through The Cancer Genome Atlas (TCGA) database, we analyzed S100A16 and its associated regulatory gene expression network in cervical cancer. We further screened genes co-expressed with S100A16 to hypothesize their function and relationship to the S100A16 cervical cancer phenotype.Our results showed that data mining can effectively elucidate the expression and gene regulatory network of S100A16 in cervical cancer, laying the foundation for further investigations into S100A16 cervical tumorigenesis.

The mitochondrial fusion-associated protein MFN2 can be used as a novel prognostic molecule for clear cell renal cell carcinoma

BackgroundMitofusin 2 (MFN2) plays an important role in many tumors, but how its role in renal clear cell carcinoma needs further research.MethodsIn this study, we analyzed the expression of MFN2 in renal clear cell carcinoma tissues and normal kidney tissues through the Cancer Genome Atlas (TCGA) database and our clinical samples.Enrichment analysis was performed to determine MFN2-related pathways and biological functions. The correlation of MFN2 expression with immune cells was analyzed.The correlation of the expression of methylation and the methylation sites of MFN2 were analyzed by UALCAN and TCGA databases. Univariate / multivariate COX risk regression and Kaplan-Meier methods were used to determine the prognostic value of MFN2.Nomograms were drawn to predict overall survival (OS) at 1,3, and 5 years. We investigated the role of MFN2 in renal cancer cells using CCK 8, clone formation, wound healing assay, and methylase qPCR experiments.ResultsMFN2 is poorly expressed in renal clear cell carcinoma compared to normal kidney tissue,and is significantly negatively associated with TNM stage, histological grade and pathological stage.MFN2 was directly associated with OS after multivariate Cox regression analysis.MFN2 shows a hypomethylation state and shows a positive correlation with multiple methylation sites.Signaling pathways through functional enrichment to B-cell receptors and oxidative stress-induced senescence.Moreover, the low expression of MFN2 was positively correlated with the degree of immune cell infiltration in a variety of immune cells.In vitro experiments showed that overexpression of MFN2 significantly inhibited the proliferation and migration of renal clear cells and promoted methylation.ConclusionsIn conclusion, MFN2 can be used as a novel prognostic marker for renal clear cell carcinoma and requires further investigation of its role in tumor development.

OR16-04 Androgen Deprivation Restricts Anti-tumor Immunity In Adrenocortical Carcinoma

Abstract Disclosure: K.M. Warde: None. L. Smith: None. C.J. Stubben: None. P.W. Willet: None. G. Castaneda-Hernandez: None. L. Liu: None. K. Basham: None. Adrenocortical carcinoma (ACC) is a rare cancer that is often diagnosed late and progresses rapidly, resulting in routinely poor outcomes. Through The Cancer Genome Atlas (TCGA) and other genomic studies, homozygous loss of ZNRF3 was newly identified as a frequent genetic alteration in human ACC tumors. ZNRF3 is an E3 ubiquitin ligase that negatively regulates Wnt signaling by degrading Wnt receptors. To examine the role of ZNRF3 in adrenal biology, we generated a Znrf3 conditional knockout (cKO) mouse model. Despite roust early hyperplasia, we found that Znrf3 cKO mice only develop adrenal tumors with advanced aging. Moreover, tumors emerge in a sex dimorphic manner whereby males, who exhibit a high myeloid immune response, predominately get benign tumors and females, who have a dampened myeloid response, develop metastatic ACC. This phenomenon is reflected clinically in patients whereby the incidence of ACC is up to 2.5x higher in women compare to men. In human ACC patients, females exhibit a lower myeloid signature compared to males. Moreover, a low myeloid response signature is associated with shorter progression-free and overall survival. These data suggest a potential relationship between anti-tumor immunity and sex in ACC, yet the underlying mechanisms remain unclear. Sex differences are common in cancer, and although there are many potential factors, gonadal hormones including androgens and estrogens, have been implicated as major biological drivers. Previous studies of the adrenal cortex highlight a specific role for androgens in repressing stem cell recruitment and proliferation. We hypothesized androgens promote anti-tumor immunity to help protect against ACC. To test this hypothesis, we castrated male Znrf3 cKO mice to lower androgen levels. We found that androgen deprivation significantly reduced myeloid cell infiltration, resulting in significantly larger adrenals in castrated as compared to sham controls. RNA-seq analysis revealed a decrease in immune activation pathways and monocyte-derived myeloid cell populations. Additionally, pro-inflammatory cytokines, including TNF, INFG, and IL-6, were significantly inhibited in castrated animals compared to controls. These data support a protective role for androgens in ACC through driving an intra-adrenal myeloid immune response. Consistent with these results, analysis of the TCGA-ACC patient cohort demonstrated that high androgen receptor expression is associated with better overall survival. Taken together, our results reveal an important role for androgens in promoting anti-tumor immunity in a mouse model of ACC, and we highlight the prognostic value of androgen receptor expression in patients. Further understanding of androgen signaling and downstream biological mechanisms that regulate the immune response may ultimately offer novel therapeutics and improve patient outcomes in ACC. Presentation: Friday, June 16, 2023

High LYRM4-AS1 predicts poor prognosis in patients with glioma and correlates with immune infiltration.

Many researches proved that non-coding RNAs are important in glioma development. We screened the differentially expressed genes through The Cancer Genome Atlas (TCGA) database and identified the molecule LYRM4-AS1 associated with prognosis. As a lncRNA, the expression level and role of LYRM4-AS1 in glioma are inconclusive. Therefore, we attempted to assess the clinical significance, expression and related mechanisms of LYRM4-AS1 in glioma by employing cell experiments and an integrative in silico methodology. RNA-seq data were obtained from UCSC XENA and TCGA datasets. The Gene Expression Omnibus (GEO) database was used to download glioma-related expression profile data. The LYRM4-AS1 expression level was evaluated. Survival curves were constructed by the Kaplan-Meier method. Cox regression analysis was used to analyze independent variables. Patients were divided into high and low expression group base on the median LYRM4-AS1 expression value in glioma tissues. The DESeq2 R package was used to identify differentially expressed genes (DEGs) between two different expression LYRM4-AS1 groups. Gene set enrichment analysis (GSEA) was conducted. Next, the single-sample Gene Set Enrichment Analysis (ssGSEA) was done to quantify the immune infiltration of immune cells in glioma tissues. Gene expression profiles for glioma tumor tissues were used to quantify the relative enrichment score for each immune cell. Spearman correlation analysis was used to analyze the correlation between LYRM4-AS1 and biomarkers of immune cells as well as immune checkpoints in glioma. Finally, assays for cell apoptosis, cell viability and wound healing were conducted to evaluate the function on U87 MG and U251 cells after knocking down LYRM4-AS1. We found that LYRM4-AS1 was upregulated and related to the grade and malignancy of glioma. Survival analyses showed that high expression LYRM4-AS1 patients had poor clinical outcomes (P < 0.01). Cox regression analyses demonstrated that LYRM4-AS1 was an independent risk factor for overall survival (OS) in glioma (HR: 274 1.836; CI [1.278-2.639]; P = 0.001). Enrichment and immune infiltration analysis showed interferon signaling and cytokine-cytokine receptor interaction enriched in the LYRM4-AS1 high-expression phenotype, and LYRM4-AS1 showed significantly positively related to immune infiltration as well as immune checkpoints (P < 0.01). The knockdown of LYRM4-AS1 in U87 MG and U251 cells can inhibit migration and proliferation of cells (P < 0.05). These findings indicated that the increased LYRM4-AS1 may be useful for the diagnosis and prognosis of glioma and might participate in the immune infiltration.

MCM6 is a Poor Prognostic Biomarker and Promotes Progression in Breast Cancer.

Breast cancer is the commonest global malignancy and the primary cause of carcinoma death. MCM6 is vital to carcinogenesis, but the pathogenesis of MCM6 remains unclear. MCM6 expression in patients with breast cancer was examined through The Cancer Genome Atlas (TCGA) database, immunohistochemistry, Quantitative Real-Time PCR (qRT‒PCR) and Western blotting. The prognostic factors were assessed by the Kaplan‒Meier method and Cox regression. On the basis of the key factors selected by multivariable Cox regression analysis, a nomogram risk prediction model was adopted for clinical risk assessment. The TCGA database was utilized to determine how MCM6 is correlated with chemotherapy sensitivity, immune checkpoint-related genes (ICGs), tumor-infiltrating immune cells, along with tumor mutation burden (TMB) and methylation. The impact of MCM6 on carcinoma cells was investigated in terms of proliferation, cell cycle as well as migrating and invasive behavior through CCK assays, flow cytometry, wound healing assays, Transwell assays and xenotransplantation experiments. MCM6 expression was upregulated, which is closely associated with the size of the tumor (p = 0.001) and lymph node metastasis (p = 0.012) in patients with breast cancer. Multivariate analysis revealed MCM6 to be an independent risk factor for prognosis in patients with breast carcinoma. The nomograph prediction model included MCM6, age, ER, M and N stage, which displayed good discrimination with a C index of 0.817 and good calibration. Overexpression of MCM6 correlated with chemotherapy sensitivity, immune checkpoint-related genes (ICGs), tumor-infiltrating immune cells, tumor mutation burden (TMB), and methylation. Silencing MCM6 significantly inhibited proliferation, prolonged the G1 phase of the cell cycle, and restrained the proliferation, migration and invasive behavior of cancerous cells and inhibited tumor growth in vivo. Our research shows that MCM6 is highly expressed in breast cancer and can be used as an independent prognostic factor, which is expected to become a new target for the treatment of breast cancer in the future.

Based on cuproptosis-related lncRNAs, a novel prognostic signature for colon adenocarcinoma prognosis, immunotherapy, and chemotherapy response.

Introduction: Colon adenocarcinoma (COAD) is a special pathological subtype of colorectal cancer (CRC) with highly heterogeneous solid tumors with poor prognosis, and novel biomarkers are urgently required to guide its prognosis. Material and methods: RNA-Seq data of COAD were downloaded through The Cancer Genome Atlas (TCGA) database to determine cuproptosis-related lncRNAs (CRLs) using weighted gene co-expression network analysis (WGCNA). The scores of the pathways were calculated by single-sample gene set enrichment analysis (ssGSEA). CRLs that affected prognoses were determined via the univariate COX regression analysis to develop a prognostic model using multivariate COX regression analysis and LASSO regression analysis. The model was assessed by applying Kaplan-Meier (K-M) survival analysis and receiver operating characteristic curves and validated in GSE39582 and GSE17538. The tumor microenvironment (TME), single nucleotide variants (SNV), and immunotherapy response/chemotherapy sensitivity were assessed in high- and low-score subgroups. Finally, the construction of a nomogram was adopted to predict survival rates of COAD patients during years 1, 3, and 5. Results: We found that a high cuproptosis score reduced the survival rates of COAD significantly. A total of five CRLs affecting prognosis were identified, containing AC008494.3, EIF3J-DT, AC016027.1, AL731533.2, and ZEB1-AS1. The ROC curve showed that RiskScore could perform well in predicting the prognosis of COAD. Meanwhile, we found that RiskScore showed good ability in assessing immunotherapy and chemotherapy sensitivity. Finally, the nomogram and decision curves showed that RiskScore would be a powerful predictor for COAD. Conclusion: A novel prognostic model was constructed using CRLs in COAD, and the CRLs in the model were probably a potential therapeutic target. Based on this study, RiskScore was an independent predictor factor, immunotherapy response, and chemotherapy sensitivity for COAD, providing a new scientific basis for COAD prognosis management.

WIPI2 enhances the vulnerability of colorectal cancer cells to erastin via bioinformatics analysis and experimental verification.

WD Repeat Domain Phosphoinositide Interacting 2 (WIPI2) is a WD repeat protein that interacts with phosphatidylinositol and regulates multiprotein complexes by providing a b-propeller platform for synchronous and reversible protein-protein interactions assembled proteins. Ferroptosis is a novel iron-dependent form of cell death. It is usually accompanied with the accumulation of membrane lipid peroxides. Our study is to focus on investigating the effect of WIPI2 on the growth and ferroptosis of colorectal cancer (CRC) cells and its potential mechanism. We analyzed the expression of WIPI2 in colorectal cancer versus normal tissues through The Cancer Genome Atlas (TCGA), and the relationship between clinical traits and WIPI2 expression and prognosis was assessed by univariate and multifactorial cox analysis. Next, we constructed the siRNAs targeting the WIPI2 sequence si-WIPI2 to further investigate the mechanism of WIPI2 in CRC cells through vitro experiments. Public data from the TCGA platform showed that WIPI2 expression was significantly elevated in colorectal cancer tissues compared to paracancerous tissues, and high WIPI2 expressionpredicted poor prognosis for CRC patients. Moreover, we found that the knockdown of WIPI2 expression could inhibit the growth and proliferation of HCT116 and HT29 cells. Furthermore, we found that the expression level of ACSL4 decreased and that of GPX4 increased when WIPI2 was knocked down, suggesting that WIPI2 can potentially positively regulate CRC ferroptosis. Meanwhile, both NC and si groups were able to further inhibit cell growth activity, as well as increase WIPI2 and decrease GPX4 expression when treated with Erastin, but the rate of cell viability inhibition and the trend of protein changes were more significantly in the NC group than si groups, which indicated that Erastin induced CRC ferroptosis through the WIPI2/GPX4 pathway thereby enhancing the sensitivity of colorectal cancer cells to Erastin. Our study suggested that WIPI2 had a promotional effect on the growth of colorectal cancer cells, and it also played an important role in the ferroptosis pathway.

GRN is a prognostic biomarker and correlated with immune infiltration in glioma: A study based on TCGA data.

Among primary brain tumors, gliomas are associated with a poor prognosis and a median survival that varies depending on the tumor grade and subtype. As the most malignant form of glioma, glioblastoma (GBM) constitutes a significant health concern. Alteration in granulin(GRN) has been proved to be accountable for several diseases. However, the relationship between GRN and GBM remains unclear. We evaluated the role of GRN in GBM through The Cancer Genome Atlas (TCGA) database. First, we assessed the relationship between GRN and GBM through the GEPIA database. Next, the relationship between GRN and GBM prognosis was analyzed by logistic regression and multivariate cox methods. Using CIBERSORT and the GEPIA correlation module, we also investigated the link between GRN and immune infiltrates in cancer. Using the TCGA data, a gene set enrichment analysis (GSEA) was performed. We also employed Tumor Immune Estimation Resource (TIMER) to examine the data set of GRN expression and immune infiltration level in GBM and investigate the cumulative survival in GBM. We also validated tissues from GBM patients by Western blotting, RT-qPCR, and immunohistochemistry. Increased GRN expression was shown to have a significant relationship to tumor grade in a univariate study utilizing logistic regression. Furthermore, multivariate analysis disclosed that GRN expression down-regulation is an independent predictive factor for a favorable outcome. GRN expression level positively correlates with the number of CD4+ T cells, neutrophils, macrophages, and dendritic cells (DCs) that infiltrate a GBM. The GSEA also found that the high GRN expression phenotype pathway was enriched for genes involved in immune response molecular mediator production, lymphocyte-mediated immunity, cytokine-mediated signaling pathway, leukocyte proliferation, cell chemotaxis, and CD4+ alpha beta T cell activation. Differentially enriched pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) include lysosome, apoptosis, primary immunodeficiency, chemokine signaling pathway, natural killer cell-mediated cytotoxicity, and B cell receptor signaling pathway. Validated result showed that GRN was upregulated in GBM tissues. These results suggested that GRN was a potential indicator for the status of GBM. GRN is a prognostic biomarker and correlated with immune infiltrates in GBM.

MP17-16 COMPARING INTRADUCTAL CARCINOMA OF THE PROSTATE TO GRADE AND STAGE: A COPY NUMBER ALTERATION CHARACTERIZATION STUDY

You have accessJournal of UrologyCME1 Apr 2023MP17-16 COMPARING INTRADUCTAL CARCINOMA OF THE PROSTATE TO GRADE AND STAGE: A COPY NUMBER ALTERATION CHARACTERIZATION STUDY Helen Pantazopoulos, Afnan Al-Saleh, Mame Kany Diop, David Boucher Roy, Roy Nitulescu, Roula Albadine, and Dominique Trudel Helen PantazopoulosHelen Pantazopoulos More articles by this author , Afnan Al-SalehAfnan Al-Saleh More articles by this author , Mame Kany DiopMame Kany Diop More articles by this author , David Boucher RoyDavid Boucher Roy More articles by this author , Roy NitulescuRoy Nitulescu More articles by this author , Roula AlbadineRoula Albadine More articles by this author , and Dominique TrudelDominique Trudel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003237.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is the most diagnosed cancer in North American men varying greatly at clinical presentation from indolent to aggressive tumors. An aggressive subtype of PCa is intraductal carcinoma of the prostate (IDC-P), identified in ∼20% of men with PCa. While accurate stratification of these high-risk patients is a clinical necessity, the question arose whether IDC-P could be related to the grade or not. We hypothesized that through the genomic characterization of IDC-P, we could explore the link between IDC-P, grade, and or stage. The objective of this study was to characterize the copy number alterations (CNAs) of IDC-P to aid in the characterization of these high-risk men, while exploring whether IDC-P should be integrated into the grade or stage of PCa. METHODS: We selected 462 radical prostatectomy specimens obtained through The Cancer Genome Atlas (TCGA). Specifically, 38 patients were excluded from the original TCGA cohort (n=500) due to stage T4 and incomplete genomic data. We further characterized the TCGA cohort by identifying the IDC-P status (present or not identified) for each patient through the online available tissue. For each patient, IDC-P status was evaluated alongside the CNAs of 488 genes involved in androgen receptor signaling and or carcinogenesis. RESULTS: Out of 462 patients, 41% (191/462) were IDC-P present, and these patients were mostly of high grade (53.9%) and advanced pT3b stage (38.7%). Overall, 38 genes were significantly associated to IDC-P growth, of which, 37 genes were novel and not unique to IDC-P or documented in PCa. Specifically, 10 genes were associated to chromosome 10q deletions, including the well-recognized PTEN, while 28 genes were associated to chromosome 8q amplifications. Of the IDC-P present men identified, 36% (69/191) of these men had multiple deletions and 16% (31/191) of these men had multiple amplifications. CONCLUSIONS: We found significant deletions in 10 genes and amplifications in 28 genes in IDC-P. Importantly, high-risk men with IDC-P have numerous deletions and amplifications in the identified 38 genes. We have identified novel genes, except for PTEN. Indeed, more than 2/3 of these genes are amplified on 8q and their expression could be targeted as biomarkers of IDC-P. We are exploring the presence of these anomalies in PCa and their relation to Grade group (especially cribriform pattern) and or stage. Together, these findings will genomically characterize IDC-P and allow for improved precision in the stratification of these high-risk patients. Source of Funding: Institut du Cancer de Montréal © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e219 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Helen Pantazopoulos More articles by this author Afnan Al-Saleh More articles by this author Mame Kany Diop More articles by this author David Boucher Roy More articles by this author Roy Nitulescu More articles by this author Roula Albadine More articles by this author Dominique Trudel More articles by this author Expand All Advertisement PDF downloadLoading ...

TEDC2 correlated with prognosis and immune microenvironment in lung adenocarcinoma

Tubulin epsilon and delta complex 2 (TEDC2) is a protein coding gene whose functions are poorly identified yet. This study aimed to identify the role of TEDC2 in prognosis and immune microenvironment of lung adenocarcinoma (LUAD). Through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, the mRNA expression of TEDC2 was upregulated in LUAD tissues compared to normal tissues. The protein level of TEDC2 was also higher in LUAD in the Human Protein Atlas. The receiver operating characteristic (ROC) curve showed that high TEDC2 level could distinguish LUAD patients from normal subjects. In addition, the impact of TEDC2 expression on prognosis was evaluated by Kaplan–Meier and Cox regression analyses, and the results suggested that high TEDC2 expression was significantly associated with poor prognosis and was the independent prognostic factor in LUAD. GO and KEGG pathway analyses indicated the co-expressed genes of TEDC2 were mainly related to mitotic cell cycle processes. Importantly, high expression of TEDC2 indicated low infiltration of immune cells, especially dendritic cells and B cells. TEDC2 was also positively correlated with immune checkpoints such as PDCD1, LAG3 and CD276. Taken together, this study preliminarily revealed the clinical significance of TEDC2 in LUAD and provided novel insights into the role of TEDC2 in immune microenvironment.

Comprehensive Analysis of Epigenetic Associated Genes with Differential Gene Expression and Prognosis in Gastric Cancer.

Gastric cancer (GC) is the most common malignancy of the human digestive system and represents the second leading cause of cancer-related deaths. As early GC is generally mild or asymptomatic and advanced GC is commonly diagnosed, early detection has a significant impact on clinical outcomes. This study aimed to identify epigenetic factors (EFs) as potential GC biomarkers. We identified 3572 differential expressed genes (DEGs) from 436 GC tissues and 41 non-tumor adjacent samples through The Cancer Genome Atlas (TCGA) datasets. Among them, a total of 57 overlapped genes were identified as differentially expressed EFs (DE-EFs), including 25 up-regulated DE-EFs and 32 down-regulated DE-EFs. Then, Gene Ontology (GO) enrichment analysis revealed that the DE-EFs were mainly associated with histone modification, chromatin remodeling, histone binding, modificationdependent protein binding, etc. Meanwhile, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results suggested that RNA degradation, thermogenesis, shigellosis, insulin resistance, AMPK, and FoxO signaling pathways play roles in the progression of GC. Subsequently, Cox regression and Kaplan-Meier analysis showed that higher expression levels of the three hub EFs, including BRCC3, USP12, and WAC, were associated with better patients' OS. We also found that GC patients in the TCGA dataset with the earlier stage of TNM stage, invasion, depth of tumor, lymph node metastasis, distant metastasis, and younger age had significantly better GC patients' OS. Furthermore, as the pathway enrichment analysis showed that BRCC3 participated in NOD-like receptors (NLRs)-mediated signaling and the homologous recombination (HR) pathways, strong and statistically significant positive relationships were found between BRCC3 with genes in NLRs signaling and HR pathways, including BRCA1, BRCA2, Rad51, BRE, TOPBP1, HSP90AA1, CASP1, NEK7, and SUGT1, respectively. We found three hub EFs, namely BRCC3, USP12, and WAC, which were downregulated in GC tissues compared to normal tissues, associated with the overall survival of GC patients and could be used as potential biomarkers to predict prognosis in GC patients. The regulation of hub genes in GC may promote the exploration of the epigenetic mechanisms associated with tumorigenesis and provide potential targets for GC diagnosis and treatment.

Abstract P1-06-07: Interrogating the Molecular Profile of Breast Cancer Tumors in Hispanics Living in Puerto Rico (PRH)

Abstract Breast cancer (BC) has the highest incidence and mortality rates among Puerto Rican women. However, the representation of Hispanics living in Puerto Rico (PRH) in breast cancer clinical trials may be limited due to the lack of a defined genetic profile from BC tumors in Puerto Rican patients. Mutations in genes associated with tumor suppressors, tumor progression, and genome stability are shared among all BCs. Nonetheless, differences in the frequency of these mutations have been observed among racial/ethnic groups. This study aims to characterize the genomic landscape of BC tumors in PRH and identify the most common genetic mutations. We conducted secondary data analysis to evaluate the mutational profile of 189 BC tumors from PRH who underwent NGS testing from 2015 to 2020 and compared the prevalence of breast tumor somatic mutations and gene amplifications with profiles reported for other races/ethnicities available through The Cancer Genome Atlas (TCGA) and the AACR Genomics Evidence Neoplasia Information Exchange (GENIE). The most mutated genes among PRH breast tumors were TP53, PIK3CA, ARID1A, NF1, and RB1, while the most frequent gene amplifications were FGF19, H3F3B, ZN703, MCL1, and ADGRA2. H1047R and E545K were the most frequent specific mutations in PRH for PIK3CA; R248Q and R273C for TP53 and Q1212*, S634* and Q557fs for ARID1A. Statistically significant differences were found between populations. This study reports a unique mutational profile of BC tumors in PRH and makes comparisons with non-Hispanic and USH populations, providing novel knowledge to increase Hispanic representation in future BC studies and treatments. Citation Format: Norianne Martinez-Viota, Xavier Bittman-Soto, Ingrid M. Montes-Rodriguez, Kelvin Carrasquillo, Hilmaris Centeno-Girona, Marcia Cruz-Correa. Interrogating the Molecular Profile of Breast Cancer Tumors in Hispanics Living in Puerto Rico (PRH) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-06-07.