AUNIP was a candidate marker for prognosis and immunology in pan-cancer

EIF5A2, a key member of the EIF family, has not been extensively studied regarding its role and mechanism in pan-cancer. TCGA and GTEx analyses were performed to investigate the differential expression of EIF5A2 in tumors and normal tissues. cBioportal was used to investigate the gene alterations of EIF5A2 in tumors. We used Cox regression and Kaplan–Meier analyses to discuss the impact of EIF5A2 expression on prognosis. Quantitative real-time PCR (qRT-PCR) was used to detect EIF5A2 mRNA levels in 12 cases of fresh liver hepatocellular carcinoma (LIHC) and corresponding adjacent non-tumor tissues. Immunohistochemistry (IHC) was employed to evaluate the expression levels of EIF5A2 in 284 cases of LIHC as well as in adjacent non-tumorous tissues. Furthermore, the study explored the association between EIF5A2 expression and various clinicopathological parameters, along with its prognostic implications. Spearman correlation analysis was used to estimate the relationship between EIF5A2 expression and tumor mutation burden (TMB), microsatellite instability (MSI), and immunologic features. “pRRophetic”R package was utilized to obtain the sensitivity of common drugs. The Gene Set Enrichment Analysis (GSEA) was used to study the functional enrichment analysis of EIF5A2-related genes. EIF5A2 was overexpressed in most tumors using TCGA and GTEx databases. Cox regression analysis demonstrated that high EIF5A2 expression was associated with unfavorable overall survival (OS) and disease-specific survival (DSS) in head and neck squamous cell carcinoma (HNSC), brain lower grade glioma (LGG), and LIHC. The frequency of EIF5A2 gene alterations was the highest in lung squamous cell carcinoma (LUSC). EIF5A2 expression was associated with TMB, MSI, and immune cell infiltration in some tumors. We performed IHC and qRT-PCR to evaluate EIF5A2 expression in HCC and normal tissues, and found upregulation of EIF5A2 expression at the mRNA and protein levels in LIHC. There was a correlation between EIF5A2 expression and tumor size, tumor grade, and TNM stage in LIHC. Kaplan–Meier survival suggested that the overexpression EIF5A2 group had unfavorable outcomes in LIHC. EIF5A2 expression was correlated with immune cell infiltration in LIHC. The high EIF5A2 expression group was more sensitive to cisplatin, crizontinib, gemcitabine, and nilotinib in LIHC. High EIF5A2 expression was associated with several pathways, including cell cycle, proteasome, DNA replication, primary immunodeficiency and oocyte meiosis. EIF5A2 may serve as a potential prognostic marker and a latent focus for cancer immunological treatment.

BackgroundNecroptosis is a novel programmed cell death mode independent on caspase. A number of studies have revealed that the induction of necroptosis could act as an alternative therapeutic strategy for drug-resistant tumors as well as affect tumor immune microenvironment.MethodsGene expression profiles and clinical data were downloaded from XENA-UCSC (including The Cancer Genome Atlas and Genotype-Tissue Expression), Gene Expression Omnibus, International Cancer Genome Consortium and Chinese Glioma Genome Atlas. We used non-negative matrix factorization method to conduct tumor classification. The least absolute shrinkage and selection operator regression was applied to establish risk models, whose prognostic effectiveness was examined in both training and testing sets with Kaplan–Meier analysis, time-dependent receiver operating characteristic curves as well as uni- and multi-variate survival analysis. Principal Component Analysis, t-distributed Stochastic Neighbor Embedding and Uniform Manifold Approximation and Projection were conducted to check the risk group distribution. Gene Set Enrichment Analyses, immune infiltration analysis based on CIBERSORT, EPIC, MCPcounter, ssGSEA and ESTIMATE, gene mutation and drug sensitivity between the risk groups were also taken into consideration.ResultsThere were eight types of cancer with at least ten differentially expressed necroptosis-related genes which could influence patients’ prognosis, namely, adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), pancreatic adenocarcinoma (PAAD), liver hepatocellular carcinoma (LIHC), skin cutaneous melanoma (SKCM) and thymoma (THYM). Patients could be divided into different clusters with distinct overall survival in all cancers above except for LIHC. The risk models could efficiently predict prognosis of ACC, LAML, LGG, LIHC, SKCM and THYM patients. LGG patients from high-risk group had a higher infiltration level of M2 macrophages and cancer-associated fibroblasts. There were more CD8+ T cells, Th1 cells and M1 macrophages in low-risk SKCM patients’ tumor microenvironment. Gene mutation status and drug sensitivity are also different between low- and high-risk groups in the six cancers.ConclusionsNecroptosis-related genes can predict clinical outcomes of ACC, LAML, LGG, LIHC, SKCM and THYM patients and help to distinguish immune infiltration status for LGG and SKCM.

Nuclear factor, erythroid 2 like 2 (NFE2L2, NRF2) is a transcription factor that regulates various antioxidant enzymes. It plays a vital physiological role in regulating oxidative stress and inflammatory response. However, the roles of NFE2L2 in human cancers are still unclear. Our study is aimed at analyzing the prognostic value of NFE2L2 in pan-cancer and at revealing the relationship between NFE2L2 expression and tumor immunity. The present study revealed that NFE2L2 was abnormally expressed and significantly correlated with mismatch repair (MMR) gene mutation levels and DNA methyltransferase expression in human pan-cancer. In particular, pan-cancer survival analysis indicated that NFE2L2 expression was associated with adverse outcomes—overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI)—in adrenocortical carcinoma (ACC), brain lower grade glioma (LGG), and pancreatic adenocarcinoma (PAAD) patients. A positive relationship was also found between NFE2L2 expression and immune infiltration, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, especially in breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), kidney renal clear cell carcinoma (KIRC), LGG, liver hepatocellular carcinoma (LIHC), and prostate adenocarcinoma (PRAD). Additionally, NFE2L2 expression was positively correlated with the immune score and the expression of immune checkpoint markers in LGG. In conclusion, these results indicate that transcription factor NFE2L2 is a potential prognostic biomarker and is correlated with immune infiltration in LGG.

Histocompatibility Minor 13 (HM13) encoding the signal peptide peptidase plays an important role in maintaining protein homeostasis but its role in tumors remains unclear. In this study, 33 tumor RNA-seq datasets were extracted from The Cancer Genome Atlas (TCGA) database, and the pan-cancer expression profile of HM13 was evaluated in combination with The Genotype-Tissue Expression (GTEx) datasets. The prognostic significance of abnormal HM13 pan-cancer expression was evaluated by univariate Cox regression and Kaplan-Meier analyses. Co-expression analysis was performed to examine the correlation between abnormal pan-cancer expression of HM13 and immune cell infiltration, immune checkpoint, molecules related to RNA modification, tumor mutational burden (TMB), microsatellite instability (MSI), and other related molecules. CellMiner database was used to evaluate the relationship between the expression of HM13 and drug sensitivity. The results showed overexpression of HM13 in almost all tumors except kidney chromophobe (KICH). Abnormally high expression of HM13 in adrenocortical carcinoma (ACC), kidney renal papillary cell carcinoma (KIRP), uveal melanoma (UVM), liver hepatocellular carcinoma (LIHC), brain lower grade glioma (LGG), head and neck squamous cell carcinoma (HNSC), and kidney renal clear cell carcinoma (KIRC) was associated with poor prognosis. Expression of HM13 correlated strongly with pan-cancer immune checkpoint gene expression and immune cell infiltration. Drug sensitivity analysis indicated that the expression of HM13 was an excellent predictor of drug sensitivity. We verified that both mRNA and protein levels of HM13 were abnormally upregulated in HCC tissues, and were independent risk factors for poor prognosis. Furthermore, interference with HM13 expression in Huh-7 and HCCLM3 cells significantly inhibited proliferation, migration, and invasion. Therefore, our findings demonstrate that HM13 is a potential pan-cancer prognostic marker, thus providing a new dimension for understanding tumor development.

Background: The tumor microenvironment (TME) consists of heterogeneous cell populations, including malignant cells and nonmalignant cells that support tumor proliferation, invasion, and metastasis through extensive cross talk. The intra-tumor immune landscape is a critical factor influencing patient survival and response to immunotherapy.Methods: Gene expression data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. Immune cell infiltration was determined by single-sample Gene Set Enrichment Analysis (ssGSEA) depending on the integrated immune gene sets from published studies. Univariate analysis was used to determine the prognostic value of the infiltrated immune cells. Least absolute shrinkage and selection operator (LASSO) regression was performed to screen for the most survival-relevant immune cells. An immune-cell characteristic score (ICCS) model was constructed by using multivariate Cox regression analysis.Results: The immune cell infiltration patterns across 32 cancer types were identified, and patients in the high immune cell infiltration cluster had worse overall survival (OS) but better progression-free interval (PFI) compared to the low immune cell infiltration cluster. However, immune cell infiltration showed inconsistent prognostic value depending on the cancer type. High immune cell infiltration (High CI) indicated a worse prognosis in brain lower grade glioma (LGG), glioblastoma multiforme (GBM), and uveal melanoma (UVM), and favorable prognosis in adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), sarcoma (SARC), and skin cutaneous melanoma (SKCM). LUAD prognosis was significantly influenced by the infiltration of 13 immune cell types, with high infiltration of all but Type 2 T helper (Th2) cells correlating with a favorable prognosis. The ICCS model based on six most survival-relevant immune cell populations was generated that classified patients into low- and high-ICCS groups with good and poor prognoses, respectively. The multivariate and stratified analyses further revealed that the ICCS was an independent prognostic factor for LUAD.Conclusions: The infiltration of immune cells in 32 cancer types was quantified, and considerable heterogeneity was observed in the prognostic relevance of these cells in different cancer types. An ICCS model was constructed for LUAD with competent prognostic performance, which can further deepen our understanding of the TME of LUAD and can have implications for immunotherapy.

BackgroundProgrammed Cell Death 2 Like (PDCD2L) correlates with cell proliferation, apoptosis and mouse embryonic development. However, the role of PDCD2L in human cancers is unclear.MethodsMultiple bioinformatic methods, in vitro function experiments and validation were performed to clarify the oncogenic role of PDCD2L in human cancers.ResultsOur study found that PDCD2L was aberrantly expressed in multiple types of human cancers, and associated with clinical stage and molecular subtype. Furthermore, overexpression of PDCD2L predicted poor overall survival in adrenocortical carcinoma(ACC), kidney chromophobe(KICH), acute myeloid leukemia(LAML), brain lower grade glioma(LGG),liver hepatocellular carcinoma(LIHC), mesothelioma(MESO), uveal melanoma(UVM) and poor diseases free survival in ACC, bladder urothelial carcinoma(BLCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), kidney renal clear cell carcinoma(KIRC), kidney renal papillary cell carcinoma(KIRP), LGG, LIHC, and UVM. PDCD2L expression was negatively associated with cancer associated fibroblast in breast invasive carcinoma (BRCA), lung squamous cell carcinoma (LUSC), sarcoma (SARC), stomach adenocarcinoma (STAD) and testicular germ cell tumors (TGCT). Mechanically, we found that PDCD2L expression was associated with apoptosis, invasion and cell cycle by investigating single cell sequencing data. For further validation, PDCD2Lwas highly expressed in colorectal cancer (CRC) cell lines and tissue samples compared with the normal colon cell line and non-tumor adjacent colorectal mucosa tissues. PDCD2L knockdown induced the apoptosis and proliferation of CRC cells.ConclusionsOur study shows that the oncogenic role of PDCD2L in various cancers and PDCD2L could be served as a biomarker of CRC.

Background: Serpin peptidase inhibitor clade H, member 1 (SERPINH1) is a gene encoding a member of the serpin superfamily of serine proteinase inhibitors. The upregulated of SERPINH1 was associated with poor prognosis in breast cancer, stomach adenocarcinoma, and esophageal carcinoma. However, the role of SERPINH1 in pan-cancer is largely unexplored. Methods: SERPINH1 expression and the correlation with prognosis in human pan-cancer were analyzed by the Cancer Genome Atlas and the Genotype-Tissue Expression dataset. Pearson correlation analysis was applied to evaluate the role of SERPINH1 expression in tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), DNA methyltransferase, and common immunoregulators. Spearman’s correlation test was used to analysis SERPINH1 expression in tumor immune infiltration and infiltrating immune cells via the Tumor Immune Evaluation Resource database. Furtherly, immunohistochemistry staining of SERPINH1 was acquired from the Human Protein Atlas database for validation. Results: SERPINH1 was abnormally expressed in fourteen cancers. The high expression of SERPINH1 significantly reduced the overall survival (OS), disease-specific survival, and progression free interval in eleven cancers. Moreover, SERPINH1 expression was correlated with MMR, MSI, TMB, and DNA methylation in multiple types of cancer. Also, SERPINH1 expression showed strong association with immunoregulators and immune checkpoint markers in testicular germ cell tumors, brain lower grade glioma (LGG), pheochromocytoma and paraganglioma. In addition, SERPINH1 expression was related to immune cell infiltration in multiple cancers, particularly in breast invasive carcinoma, LGG, and liver hepatocellular carcinoma. The result of immunohistochemistry verification shown that SERPINH1 staining was higher in tumor samples than in normal tissue in colon adenocarcinoma, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma and cervical squamous cell carcinoma, which was consistent with the result of OS. Conclusion: Overall, these results indicate that SERPINH1 may serve as an important prognostic biomarker and correlate with tumor immunity in human pan-cancer.

TTC39A (tetratricopeptide repeat domain protein 39A) belongs to the structural family of tetratrico-peptide domain proteins. TTC39A had not been researched in cancers. The purpose of this study was to reveal the potential role of TTC39A in cancers. In total, 33 cancers were included in this study. All the data came from the Cancer Genome Atlas (TCGA) database. The expression of TTC39A was explored in the 33 cancers. The relationship between the expression of TTC39A and prognosis, clinical characteristics, and immune infiltration was also explored. Paraffin-embedded cancer tissue microarrays (TMA) were used to detect the expression of TTC39A in LIHC (liver hepatocellular carcinoma) and LGG (brain lower grade glioma). The expression of TTC39A was higher in many cancers, compared with the corresponding normal tissues. For patients with LGG, LIHC, and SKCM (skin cutaneous melanoma), higher expression of TTC39A indicated worse OS. Survival analysis in clinical samples indicated that high expression of TTC39A was associated with shorter overall survival. The expression of TTC39A was related to the immune infiltration of some immune cells in LGG, LIHC, and SKCM. Also, the expression of TTC39A combined with the immune infiltration level of some immune cells could affect the OS of patients with these three cancers. Functional enrichment analysis and gene set enrichment analysis (GSEA) showed that TTC39A might play a role in many biological processes. The expression of TTC39A was significantly higher in many cancers. TTC39A was associated with the prognosis of patients with LGG, LIHC, and SKCM, whether they were combined with the immune infiltration level of some immune cells or not. In these three cancers, TTC39A might play a role in some important biological processes.

Purpose: Hypoxia is widely recognized as a determiner in cancer. Cysteamine dioxygenase (ADO) is demonstrated to be a novel oxygen sensor, globally expressed in animals and plants. However, the functions of ADO in human cancers remain unclear. This study was to identify the survival association of ADO in cancers and to excavate its underlying mechanisms. Methods: Transcriptional expression profiles, clinical characteristics, single nucleotide variation (SNV) data, and 450K methylation data were downloaded from all cancer types in the cancer genome atlas (TCGA). Two independent liver cancer datasets GSE14520 and GSE36376 were downloaded for further validation. Results: The expression of ADO gene was differentially expressed in various cancers. High expression of ADO indicated a worse OS and PFS in adrenocortical carcinoma (ACC), acute myeloid leukemia, liver hepatocellular carcinoma (LIHC), while predicted better OS and PFS in brain lower-grade glioma (LGG), and kidney renal clear cell carcinoma (KIRC). Across various cancers, ADO was positively correlated with tumor-associated pathways including G2/M_checkpoint, MYC_targets, and TGFB while negatively correlated with Genes_upregulated_by_reactive_oxygen_species (ROS) through ssGSEA analysis. The expression of ADO gene was highly correlated with hypoxic marker HIF1A, HIF2A, KDM5A, and KDM6A in almost all cancer types while poorly correlated with Hallmark_hypoxia geneset and Regulation_of_cellular response_to_hypoxia geneset, which indicated that ADO might work independently with HIF1A-mediated response. ADO was positively correlated with the methylation of most chromatin regulators in LGG and LIHC. ADO expression positively correlated with most immune checkpoint molecules in most cancers. Notably, a highly positive correlation between ADO and CD276, ENTPD1, or HMGB1 was observed in most cancer types. In liver cancer, ADO was positively correlated with the infiltration of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, myeloid dendritic cells. However, ADO expression was not strongly relevant to TMB in liver cancer. The increased expression, poor survival indication and immune checkpoint correlation of ADO in liver cancer were further validated by GSE14520 and GSE36376 datasets. Conclusion: ADO was differentially expressed in various cancers and significantly associated with survival in some cancer types including liver cancer. The underlying mechanism might be associated with the G2/M checkpoint, MYC targets and TGFB pathways, and ADO-mediated HIF1A-independent hypoxic response. The immune cell infiltrates and immune checkpoints association hints that ADO might be a biomarker for immunotherapy in liver cancer. Citation Format: Jie Huang, Juan Shen, Yao Qiu, Jiannan Qian, Jiawei Li, Xueqin Chen, Shenglin Ma. The prognostic relevance and underlying mechanisms of the novel oxygen sensor ADO in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5002.

Prolyl 3-hydroxylase 1 (P3H1) has been implicated in cancer development, but no pan-cancer analysis has been conducted on P3H1. In this study, for the first time, aspects associated with P3H1, such as the mRNA expression, any mutation, promoter methylation, and prognostic significance, the relationship between P3H1 and clinicopathological parameters, drug sensitivity, and immune cell infiltration were investigated by searching several databases including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), cBioPortal, and The Tumor Immune Evaluation Resource (TIMER2.0) using bioinformatics tools. The findings indicate significant differential expression of P3H1 in most tumors when compared to normal tissues, with a strong association with clinical prognosis. A pan-cancer Cox regression analysis revealed that high P3H1 expression is significantly associated with low overall survival in patients with brain lower grade glioma, kidney clear cell carcinoma, adrenocortical cancer, liver hepatocellular carcinoma, mesothelioma, sarcoma, uveal melanoma, bladder urothelial carcinoma, kidney papillary cell carcinoma, kidney chromophobe, thymoma, and thyroid carcinoma. A negative correlation was observed between P3H1 DNA methylation and its expression. P3H1 is significantly associated with infiltrating cells, immune-related genes, tumor mutation burden, microsatellite instability, and mismatch repair. Finally, A significant correlation was found between P3H1 expression and sensitivity to nine drugs. Thus, enhanced P3H1 expression is associated with poor prognosis in a variety of tumors, which may be due to its role in tumor immune regulation and tumor microenvironment. This pan-cancer analysis provides insight into the function of P3H1 in tumorigenesis of different cancers and provides a theoretical basis for further in-depth studies to follow.

Forkhead box J3 (FOXJ3) is a member of the forkhead box (Fox) family. Recently, increasing evidence has revealed the relationship between Fox family members and cancer. FOXJ3 is involved in various types of cancer, including lung cancer, tongue squamous carcinoma, and prostate cancer; however, a comprehensive pan-cancer analysis of FOXJ3 remains lacking. Here, we explored the function of FOXJ3 across cancers using online websites and databases including TIMER2.0, SangerBox, UALCAN, GEPIA2.0, cBioPortal, CancerSEA,STRING, BioGRID and Metascape to analyze the role of FOXJ3 in cancers. Abnormal expression of FOXJ3 was found in various tumors. The genetic alteration percentage in tumors was determined, and elevated FOXJ3 expression was found to be associated with worse overall survival in brain lower grade glioma(LGG), liver hepatocellular carcinoma (LIHC), sarcoma (SARC) and thyroid carcinoma. Elevated FOXJ3 expression was related to worse prognosis with disease-free survival in adrenocortical carcinoma, LGG and LIHC. FOXJ3 expression was related to immune infiltration in several cancers. Enrichment analysis showed that histone modification, the TGF-β signaling pathway, and chromatin organization were the top three enriched ontology clusters of the top 100 similar genes of FOXJ3. Our pan-cancer analysis provides comprehensive insights into FOXJ3 from the perspective of bioinformatics in different cancers, where it serves as a potential biomarker for prognosis, especially in LGG and LIHC. FOXJ3 is also correlated with immune infiltrates in certain human tumors.

BackgroundWAC-antisense RNA1 (WAC-AS1) is a newly identified long non-coding RNA (lncRNA) implicated in the prognosis and development of a few types of tumors. However, the correlations of WAC-AS1 with immune infiltration and patient prognosis in pan-cancer remain unclear. In the present study, we aimed to investigate the prognostic value and immunological functions of WAC-AS1 across 33 different types of cancers.MethodsTo investigate the potential oncogenic roles of WAC-AS1, bioinformatics analyses were performed using the Cancer Genome Atlas (TCGA) and Genotype Tissue-Expression (GTEx) datasets. The correlations of WAC-AS1 with prognosis, clinical phenotype, tumor mutational burden (TMB), microsatellite instability (MSI), tumor regulation-related genes, tumor microenvironment, immune cell infiltration, and drug resistance to commonly used chemotherapy drugs in different types of tumors were explored. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed to explore the biological functions of WAC-AS1 in tumors. In situ hybridization (ISH) was performed in tissue microarray (TMA) to confirm the expression of WAC-AS1 in multiple tumor tissues.ResultsWAC-AS1 showed aberrant expression in most cancers when compared to the normal tissues. It also has prognostic value in multiple types of cancers. Elevated WAC-AS1 expression was associated with poor prognosis and overall survival in adrenocortical carcinoma (ACC), breast invasive carcinoma (BRCA), and liver hepatocellular carcinoma (LIHC). A significant negative correlation between WAC-AS1 expression and overall survival was observed in brain lower-grade glioma (LGG), pancreatic adenocarcinoma (PAAD), and skin cutaneous melanoma (SKCM). The expression of WAC-AS1 also showed a correlation with clinical stage in six types of tumors, and with tumor mutational burden and microsatellite instability in several different types of cancers. The immune scores of those cancers were found to be significant. Additionally, the effectiveness of fluorouracil and four other anticancer drugs was significantly different based on the expression of WAC-AS1 in these cancers. Moreover, the ISH results showed in six types of tumors, the expression of WAC-AS1 was consistent with the Pan-cancer analysis using TCGA and GTEx database.ConclusionsThese results indicate an intensive involvement of WAC-AS1 in the regulation of immune responses, immune cell infiltration, and malignant properties in various types of cancers, suggesting that WAC-AS1 may serve as a prognostic marker across diverse types of cancers.

BackgroundPoly (ADP-ribose) polymerases-1 (PARP1) alterations are associated with PARP1 inhibitor resistance, regulating the function of Treg cells and PDL1 expression in tumor cells, and high PARP1 expression is significantly associated with aggressive behavior and chemotherapeutic resistance in several tumors. However, a comprehensive analysis of the predictive values of PARP1 alteration for immune checkpoint inhibitor (ICI) effectiveness in tumors remains unclear, and the associations between its expression and immunotherapy signatures also needs to be explored further.MethodsWe performed some analyses with the cBioPortal online database (https://www.cbioportal.org), TIMER2.0 (Tumor Immune Estimation Resource 2.0, http://timer.comp-genomics.org/) and TCGA database (https://xenabrowser.net or https://portal.gdc.cancer.gov/). Survival analysis was conducted using Kaplan–Meier method, and the associations between PARP1 transcription levels and immune checkpoint gene expression, the number of neoantigens, tumor mutation burden (TMB) levels, and microsatellite instability (MSI) event are analyzed by spearman correlation analysis and visualization of those mentioned above is performed using R, version 3.6.3 (http://www.r-project.org/).ResultsWe found that PARP1 was altered in 1338 (2.9%) out of 45604 patients with diverse tumors, which was associated with markedly higher TMB levels in a variety of tumors (P < 0.01). Impressively, patients with PARP1 alterations in advanced tumors showed better overall survival (OS) in the ICI-treated cohort (P = 0.016). PARP1 altered group was substantially correlated with higher immune infiltrates across most tumors, including CD8+ T cells in colorectal adenocarcinoma (P = 0.0061), endometrial carcinoma (P = 0.0033), stomach cancer (P = 0.033), and cervical cancer (P = 0.026), respectively. The PARP1 altered group showed high expression in transcription (P < 0.001), and higher expression of LAG3, PDCD1, CTLA-4, and TIGIT (P < 0.05). Higher PARP1 expression was present in 27 tumor compared the corresponding normal tissues using the GTEx and TCGA databases and it had a worse OS in several tumors (P < 0.05). Further, high PARP1 expression was significantly associated with six immune cells (B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells) in most tumors, including colon adenocarcinoma (COAD), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), and liver hepatocellular carcinoma (LIHC) (P < 0.05). In particular, CD8+T cell infiltration, was also positively correlated with high PARP1 expression in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), LIHC, pancreatic adenocarcinoma (PAAD), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), testicular germ cell tumors (TGCT), thymoma (THYM), uterine corpus endometrial carcinoma (UCEC), uveal melanoma (UVM) (P < 0.05, no data shown), and PARP1 expression was significantly positively correlated with the transcription levels of some of the 47 immune checkpoint genes, such as CD274, CTLA4, and PDCD1 in several tumors, including PAAD, LIHC, KIRC, HNSC, and BLCA (P < 0.05). A significant positive association between PARP1 expression and the number of immune neoantigen was found within COAD, KIRC, lung adenocarcinoma (LUAD), PAAD and THYM (P < 0.05), and there were also significantly positive correlations between PARP1 expression and TMB in many tumors like adrenocortical carcinoma (ACC), COAD, kidney chromophobe (KICH), LGG, LUAD, READ, skin cutaneous melanoma (SKCM) and stomach adenocarcinoma (STAD) (P < 0.05). In addition, high PARP1 expression was positively associated with microsatellite instability event in COAD, KIRP, BRCA, glioblastoma multiforme (GBM), lung squamous cell carcinoma (LUSC), LGG, READ, UCEC, SKCM and LUAD (P < 0.05).ConclusionsOur results highlight the significance of PARP1 alterations as pan-cancer predictive biomarkers for ICI treatment, and its expression levels seem to be correlated with the status of immunotherapy-associated signatures, thus may be a promising biomarker for predicting ICI response in several tumors.

BackgroundWilm’s tumor 1-associated protein (WTAP) is a critical component of the methyltransferase complex responsible for N6-methyladenosine (m6A) modification in RNA. This modification is involved in various cancer-related biological processes. However, the precise role of WTAP in tumor cell cycle regulation and immune responses remains poorly understood.MethodsA comprehensive analysis was conducted using multi-database resources to investigate the role of WTAP in tumorigenesis. Data from 33 tumor types were collected from the Genotype-Tissue Expression (GTEx), The Cancer Genome Atlas (TCGA), and Cancer Cell Line Encyclopedia (CCLE) databases. Correlations between WTAP expression and prognosis, immune microenvironment, immune neoantigens, immune checkpoint molecules, tumor mutation burden (TMB), and microsatellite instability (MSI) were analyzed. Additionally, Gene Set Enrichment Analysis (GSEA) was performed to explore the signaling pathways associated with WTAP expression.ResultsPan-cancer analysis revealed differential expression of WTAP across multiple tumor types compared to normal tissues. High WTAP expression was significantly associated with poor prognosis in adrenocortical carcinoma (ACC), brain lower-grade glioma (LGG), liver hepatocellular carcinoma (LIHC), and ovarian serous cystadenocarcinoma (OV). In contrast, low WTAP expression correlated with improved survival in skin cutaneous melanoma (SKCM) and thymoma (THYM). WTAP expression demonstrated a positive correlation with immune cell infiltration, including B cells, CD4 + T cells, CD8 + T cells, dendritic cells, macrophages, and neutrophils. Additionally, WTAP expression was positively associated with stromal, immune, and overall immune estimate scores. No significant association was identified between WTAP expression and immune neoantigen counts. However, WTAP expression correlated with the expression of most common immune checkpoint genes, DNA mismatch repair genes, and DNA methyltransferases. Furthermore, WTAP expression significantly influenced TMB and MSI levels. GSEA indicated that WTAP predominantly contributes to cell cycle regulation, thereby promoting tumorigenesis.ConclusionWTAP is a potential immune-related prognostic biomarker in malignancies. Its role in regulating the cell cycle and immune microenvironment highlights its influence on tumor development and progression.

Pan-cancer analysis reveals the expression, genetic alteration and prognosis of pyroptosis key gene GSDMD