Pan-Cancer Analysis Revealed SRSF9 as a New Biomarker for Prognosis and Immunotherapy

Background. Serine/arginine-rich splicing factor 9 (SRSF9) is one of the members of SRSF gene family and related to the tumorigenesis and the progression of tumor. However, whether SRSF9 has a crucial role across pan-cancer is still unknown. Methods. In this study, we used public databases, such as The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx), to analyze SRSF9 expression level among tumor and normal cells. Survival analysis, K-M plotter, and PrognoScan were used to analyze the prognosis value of SRSF9, regarding to overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). Moreover, we performed the correlation between SRSF9 and clinical characteristics (including the outcome of prognosis), as well as molecular events of tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoint gene, tumor microenvironment (TME), immune infiltrating cells, mismatch repair (MMR) genes, m6A genes, DNA methyltransferases, and neoantigen with bioinformatics methods and TISIDB, TIMER, and Sangerbox websites. Results. In general, SRSF9 expression was upregulated in most cancers, such as BLCA, CHOL, and UCEC, which SRSF9 was associated with short survival and severe progression. In COAD, STAD, and UCEC, SRSF9 expression was positively related to both TMB and MSI. In BRCA, BLCA, ESCA, GBM, HNSC, LUSC, LUAD, OV, PRAD, TGCT, THCA, and UCEC, both immune score and stomal score showed a negative relationship with SRSF9 expression. Immune score showed a positive relationship with SRSF9 expression in LGG. SRSF9 expression had a significant and positive correlation with six types of immune infiltration cells in LGG, KIRC, LIHC, PCPG, PRAD, SKCM, THCA, and THYM, except in LUSC. In LIHC, SRSF9 was highly significant correlated with most immune checkpoint genes. For neoantigens, correlation between SRSF9 and the quantity of neoantigens was significantly positive in some cancer types. SRSF9 was also correlated with MMR genes, m6A genes, and DNA methyltransferases. In the 33 cancer types, gene set enrichment analysis (GSEA) demonstrated that SRSF9 was correlated with multiple functions and signaling pathways. Conclusion. These findings demonstrated that SRSF9 may be a new biomarker for the prognosis and immunotherapy in various cancers. As a result, it will be beneficial to provide new therapies for cancer patients, thereby improving the treatment and prognosis of cancer patients.

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A pan-cancer analysis revealing the role of TIGIT in tumor microenvironment

Scientific Reports ◽

10.1038/s41598-021-01933-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jie Wen ◽

Xueyi Mao ◽

Quan Cheng ◽

Zhixiong Liu ◽

Fangkun Liu

Keyword(s):

T Cells ◽

Immune Cells ◽

Immune Checkpoint ◽

Expression Patterns ◽

Gene Set Enrichment Analysis ◽

Functional Enrichment ◽

Receptor Interaction ◽

Mmr Genes ◽

Potential Biomarker ◽

Cancer Types

AbstractT cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), an immune checkpoint, plays a pivotal role in immune suppression. However its role in tumor immunity and correlation with the genetic and epigenetic alterations remains unknown. Here, we comprehensively analyzed the expression patterns of the TIGIT and its value of prognostic prediction among 33 types of cancers based on the data collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression projects (GTEx). Furthermore, the correlations of TIGIT with pathological stages, tumor-infiltrating immune cells (TIICs), signatures of T cells subtypes, immune checkpoint genes, the degree of Estimation of STromal and Immune cells in MAlignant Tumor tissues using the Expression data (ESTIMATE), tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, and DNA methyltransferases (DNMTs) were also explored. Gene functional enrichment was conducted by Gene Set Enrichment Analysis (GSEA). Our results showed that the expression of TIGIT was upregulated in most of the cancer types. Cox regression model showed that high expression of TIGIT in tumor samples correlates with poor prognosis in KIRC, KIRP, LGG, UVM, and with favorable prognosis in BRCA, CECS, HNSC, SKCM. TIGIT expression positively correlated with advanced stages, TIICs, the signatures of effector T cells, exhausted T cells, effector Tregs and the degree of ESTIMATE in KIRC, KIRP and UVM. TIGIT expression also positively correlated with CTLA4, PDCD1 (PD-1), CD274 (PD-L1), ICOS in most of the cancer types. Furthermore, the expression of TIGIT was correlated with TMB, MSI, MMR genes and DNMTs in different types of cancers. GSEA analysis showed that the expression of TIGIT was related to cytokine-cytokine receptor interaction, allograft rejection, oxidative phosphorylation. These findings suggested that TIGIT could serve as a potential biomarker for prognosis and a novel target for immunotherapies in cancers.

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A Pan-Cancer Analysis Revealing the Role 2 of TIGIT in Tumor Microenvironment

10.21203/rs.3.rs-638517/v1 ◽

2021 ◽

Author(s):

Jie Wen ◽

Xueyi Mao ◽

Quan Cheng ◽

Zhixiong Liu ◽

Fangkun Liu

Keyword(s):

Immune Cells ◽

Immune Checkpoint ◽

Cox Regression ◽

Expression Patterns ◽

Gene Set Enrichment Analysis ◽

Functional Enrichment ◽

Receptor Interaction ◽

Mmr Genes ◽

Potential Biomarker ◽

Cancer Types

Abstract T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), an immune checkpoint, plays a pivotal role in immune suppression. However its role in tumor immunity and correlation with the genetic and epigenetic alterations remains unknown.Here, we comprehensively analyzed the expression patterns of the TIGIT and its value of prognostic prediction among 33 types of cancers based on the data collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression projects (GTEx). Furthermore, the correlations of TIGIT with tumor-infiltrating immune cells (TIICs), immune checkpoint genes, the degree of Estimation of STromal and Immune cells in MAlignant Tumor tissues using the Expression data (ESTIMATE), tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, and DNA methyltransferases (DNMTs) were also explored. Gene functional enrichment was conducted by Gene Set Enrichment Analysis (GSEA). Our results showed that the expression of TIGIT was upregulated in most of the cancer types. Cox regression model showed that high expression of TIGIT in tumor samples correlates with poor prognosis in KIRC, KIRP, LGG, UVM, and with favorable prognosis in BRCA, CECS , HNSC, SKCM. TIGIT expression significantly correlated with TIICs and the degree of ESTIMATE in KIRC, KIRP and UVM. TIGIT expression also correlated with CTLA4, PDCD1 (PD-1), CD274 (PD-L1), ICOS in most of the cancer types. Furthermore, the expression of TIGIT was correlated with TMB, MSI, MMR genes and DNMTs in different types of cancers. GSEA analysis showed that the expression of TIGIT was related to cytokine-cytokine receptor interaction, allograft rejection, oxidative phosphorylation.These findings suggested that TIGIT could serve as a potential biomarker for prognosis and a novel target for immunotherapies in cancers.

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Exploration of the MSI landscape in Chinese pan-cancer patient by Next-Generation Sequencing.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14576 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14576-e14576

Author(s):

Xinlu Liu ◽

Jiasheng Xu ◽

Jian Sun ◽

Deng Wei ◽

Xinsheng Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Correlation Analysis ◽

Cancer Patients ◽

Cancer Type ◽

Multiple Tumor ◽

Treatment Plans ◽

Cancer Types ◽

Chinese Cancer Patients ◽

Colorectal Cancer Patients ◽

Pan Cancer

e14576 Background: Clinically, MSI had been used as an important molecular marker for the prognosis of colorectal cancer and other solid tumors and the formulation of adjuvant treatment plans, and it had been used to assist in the screening of Lynch syndrome. However, there were currently few reports on the incidence of MSI-H in Chinese pan-cancer patients. This study described the occurrence of MSI in a large multi-center pan-cancer cohort in China, and explored the correlation between MSI and patients' TMB, age, PD-L1 expression and other indicators. Methods: The study included 8361 patients with 8 cancer types from multiple tumor centers. Use immunohistochemistry to detect the expression of MMR protein (MLH1, MSH2, MSH6 and PMS2) in patients with various cancer types to determine the MSI status and detect the expression of PD-L1 in patients. Through NGS technology, 831 genes of 8361 Chinese cancer patients were sequenced and the tumor mutation load of the patients was calculated. The MSI mutations of patients in 8 cancer types were analyzed and the correlation between MSI mutations of patients and the patient's age, TMB and PD-L1 expression was analyzed. Results: The test results showed that MSI patients accounted for 1.66% of pan-cancers. Among them, MSI-H patients accounted for the highest proportion in intestinal cancer, reaching 7.2%. The correlation analysis between MSI and TMB was performed on patients of various cancer types. The results showed that: in each cancer type, MSI-H patients had TMB greater than 10, and 26.83% of MSI-H patients had TMB greater than 100 in colorectal cancer patients. The result of correlation analysis showed that there was no significant correlation between the patient's age and the risk of MSI mutation ( P> 0.05). In addition to PAAD and LUAD, the expression of PD-L1 in MSI-H patients was higher than that in MSS patients in other cancer types( P< 0.05). The correlation analysis between PD-L1 expression and TMB in patients found that in colorectal cancer, the higher the expression of PD-L1, the higher the patient's TMB ( P< 0.05). Conclusions: In this study, we explored the incidence of MSI-H in pan-cancer patients in China and found that the TMB was greater than 10 in patients with MSI-H. Compared with MSS patients, MSI-H patients have higher PD-L1 expression, and the higher the PD-L1 expression in colorectal cancer, the higher the TMB value of patients.

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An ultrasensitive method for noninvasive pan-cancer early detection based on targeted methylation sequencing of cell-free DNA.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10544 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10544-10544

Author(s):

Tiancheng Han ◽

Yuanyuan Hong ◽

Pei Zhihua ◽

Song Xiaofeng ◽

Jianing Yu ◽

...

Keyword(s):

Cancer Patients ◽

Cancer Detection ◽

Real World ◽

Early Stage ◽

Validation Dataset ◽

Cpg Sites ◽

Free Dna ◽

Cancer Types ◽

Discovery Dataset ◽

Pan Cancer

10544 Background: Screening the biomarkers from the cell-free DNA (cfDNA) of peripheral blood is a non-invasive and promising method for cancer diagnosis. Among diverse types of biomarkers, epigenetic biomarkers have been reported to be one of the most promising ones. Epigenetic modifications are widespread on the human genome and generally have strong signals due to the similar methylation patterns shared by adjacent CpG sites. Although some epigenetic diagnostic methods have been developed based on cfDNAs, few of them could be applied to pan-cancer and their sensitivities are barely satisfactory for early cancer detection. Methods: Targeted methylation sequencing was performed using our in-house-designed panel targeting regions with abundant cancer-specific methylation CpGs. The cfDNA samples from 80 healthy individuals and 549 cancer patients of 14 cancer types were separately sequenced. The dataset was randomly split into one discovery dataset and one validation dataset. Moreover, cfDNA samples from four cancer patients were diluted with the healthy cfDNAs to generate 12 in vitro simulated samples with low circulating tumor DNA (ctDNA) fraction. Additionally, DNAs extracted from 130 unmatched tumor formalin fixation and paraffin embedding (FFPE) samples of 10 cancer types were sequenced to screen the diagnostic biomarkers. Adjacent CpG sites were first merged into methylation-correlated blocks (MCB) according to their correlations of methylation levels in tumor DNAs. The MCBs with higher methylation levels in tumor DNAs than that of healthy cfDNAs (from the discovery dataset) were defined as our hypermethylation biomarkers. For each cfDNA sample, a hypermethylation score (HM-score) was computed to measure the overall methylation level difference of selected biomarkers. The performance of our method was evaluated with the real-world dataset, while the limit of detection was estimated using the simulated low-ctDNA samples. Results: Our model based on 37 hypermethylation MCB biomarkers achieved an area under the curve (AUC) of 0.89 and 0.86 in the real-world pan-cancer discovery and validation cfDNA datasets, respectively. Furthermore, the overall specificity and sensitivity are 100% and 76.19% in the discovery dataset, and 96.67% and 72.86% in the validation dataset. In the validation dataset, 28/40 (70%) of early-stage colorectal cancer patients and 10/20 (50%) of non-small-cell lung cancer patients were successfully diagnosed. Additionally, all the simulated samples with theoretical ctDNA factions over 0.5% were predicted as diseased, demonstrating the ability of our method to detect tumor signals at early stages. Conclusions: Our cfDNA-based epigenetic method outperforms currently available methods in various cancer types, and is promising to be applied to early-stage cancer detection and samples with low ctDNA fractions.

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TRPV4 is a Prognostic Biomarker that Correlates with the Immunosuppressive Microenvironment and Chemoresistance of Anti-Cancer Drugs

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.690500 ◽

2021 ◽

Vol 8 ◽

Author(s):

Kai Wang ◽

Xingjun Feng ◽

Lingzhi Zheng ◽

Zeying Chai ◽

Junhui Yu ◽

...

Keyword(s):

Ovarian Cancer ◽

Transient Receptor Potential ◽

Immune Cell ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

High Expression ◽

Cancer Drugs ◽

Free Interval ◽

Anti Cancer ◽

Pan Cancer

Background: Transient receptor potential cation channel subfamily V member 4 (TRPV4) has been reported to regulate tumor progression in many tumor types. However, its association with the tumor immune microenvironment remains unclear.Methods: TRPV4 expression was assessed using data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. The clinical features and prognostic roles of TRPV4 were assessed using TCGA cohort. Gene set enrichment analysis (GSEA) of TRPV4 was conducted using the R package clusterProfiler. We analyzed the association between TRPV4 and immune cell infiltration scores of TCGA samples downloaded from published articles and the TIMER2 database. The IC50 values of 192 anti-cancer drugs were downloaded from the Genomics of Drug Sensitivity in Cancer (GDSC) database and the correlation analysis was performed.Results: TRPV4 was highly expressed and associated with worse overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI) in colon adenocarcinoma (COAD) and ovarian cancer. Furthermore, TRPV4 expression was closely associated with immune regulation-related pathways. Moreover, tumor-associated macrophage (TAM) infiltration levels were positively correlated with TRPV4 expression in TCGA pan-cancer samples. Immunosuppressive genes such as PD-L1, PD-1, CTLA4, LAG3, TIGIT, TGFB1, and TGFBR1 were positively correlated with TRPV4 expression in most tumors. In addition, patients with high expression of TRPV4 might be resistant to the treatment of Cisplatin and Oxaliplatin.Conclusion: Our results suggest that TRPV4 is an oncogene and a prognostic marker in COAD and ovarian cancer. High TRPV4 expression is associated with tumor immunosuppressive status and may contribute to TAM infiltration based on TCGA data from pan-cancer samples. Patients with high expression of TRPV4 might be resistant to the treatment of Cisplatin and Oxaliplatin.

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A pan-cancer study on characteristic of CDK4/6 amplification between Chinese and Western patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15074 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15074-e15074

Author(s):

Yamin Zhang ◽

Zilin Cui ◽

Rui Shi ◽

Xiaolong Liu ◽

Yang Li ◽

...

Keyword(s):

Soft Tissue ◽

Liver Cancer ◽

Soft Tissue Sarcoma ◽

Lung Adenocarcinoma ◽

Ovarian Carcinoma ◽

Cancer Patients ◽

Stomach Carcinoma ◽

Chinese Cohort ◽

Cancer Types ◽

Pan Cancer

e15074 Background: CDK4/6 kinases associate with cyclin D proteins during transition from G1 to S phase of the cell cycle. Amplification of CDK4/6 may elicit the activity of cyclin D, which hyperphosphorylates RB, ultimately leading to uncontrolled cell proliferation. Currently, three CDK4/6 inhibitors are used in breast cancer, ovarian cancer and sarcoma. Herein, we investigate the prevalence of CDK4/6 amplification in Chinese and Western cancer patients, hope to find more cancer subtypes with CDK4/6 amplification. Methods: Next-generation sequencing data and clinical data were collected from 10828 TCGA pan-cancer patients (Western cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 4181 Chinese pan-cancer patients (Chinese cohort). CDK4 and CDK6 amplification were calculated on the two cohorts following the same criteria. Results: In total, 182 (4.4%) of the 4181 Chinese patients and 529 (4.9%) of the 10828 Western patients had CDK4 amplification, 133 (3.2%) of the 4181 Chinese patients and 475 (4.4%) of the 10828 Western patients had CDK6 amplification. In Western cohort, the top 5 CDK4 amplification-associated cancer types were sarcoma, glioblastoma multiforme, lung adenocarcinoma, ovarian carcinoma, and adrenocortical carcinoma, and the top 5 CDK6 amplification-associated cancer types were esophageal carcinoma, ovarian carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, sarcoma. In Chinese cohort, the top 5 CDK4 amplification-associated cancer types were lung adenocarcinoma, melanoma, sarcoma, stomach carcinoma, liver cancer, and the top 5 CDK6 amplification-associated cancer types were lung adenocarcinoma, stomach carcinoma, liver cancer, melanoma, glioma. In addition, CDK4 amplification in Chinese cohort, 22 (11%) of the 203 Chinese bone and soft tissue sarcoma patients had CDK4 amplification, and 4 (2%) of the 203 had CDK6 amplification. Bone and soft tissue sarcoma types with CDK4 / 6 amplification including soft tissue sarcoma, bone cancer, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, liposarcoma, synovial sarcoma. Conclusions: Our study provided a characteristic of CDK4/6 amplification in Chinese and Western pan-cancer patients. Analysis revealed frequent CDK4 / 6 amplification in lung cancer, sarcoma, stomach carcinoma, ovarian carcinoma and liver cancer. It is suggested patient with these cancer types may potentially benefit from CDK4/6 inhibitor.

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TRPV4 is a Prognostic Biomarker That Correlates With the Immunosuppressive Microenvironment and Chemoresistance of Anti-Cancer Drugs

10.21203/rs.3.rs-383566/v1 ◽

2021 ◽

Author(s):

kai wang ◽

Jun xing Feng ◽

Zhi ling Zheng ◽

Ying ze Chai ◽

Hui jun Yu ◽

...

Keyword(s):

Ovarian Cancer ◽

Transient Receptor Potential ◽

Immune Cell ◽

Colon Adenocarcinoma ◽

Enrichment Analysis ◽

Receptor Potential ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Free Interval ◽

Pan Cancer

Abstract Background: Transient receptor potential cation channel subfamily V member 4 (TRPV4) has been reported to regulate tumor progression in many tumor types. However, its association with the tumor immune microenvironment remains unclear.Methods: TRPV4 expression was assessed using data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. The clinical features and prognostic roles of TRPV4 were assessed using TCGA cohort. Gene set enrichment analysis (GSEA) of TRPV4 was conducted using the R package clusterProfiler. We analyzed the association between TRPV4 and immune cell infiltration scores of TCGA samples downloaded from published articles and the TIMER2 database.Results: TRPV4 was highly expressed and associated with worse overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI) in colon adenocarcinoma (COAD) and ovarian cancer. Furthermore, TRPV4 expression was closely associated with immune regulation-related pathways. Moreover, tumor-associated macrophage (TAM) infiltration levels were positively correlated with TRPV4 expression in TCGA pan-cancer samples. Immunosuppressive genes such as PD-L1, PD-1, CTLA4, LAG3, TIGIT, TGFB1, and TGFBR1 were positively correlated with TRPV4 expression in most tumors.Conclusions: Our results suggest that TRPV4 is an oncogene and a prognostic marker in COAD and ovarian cancer. High TRPV4 expression is associated with tumor immunosuppressive status and may contribute to TAM infiltration based on TCGA data from pan-cancer samples.

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The prevalence of CDK12 alterations in Chinese cancer patients and the association with tumor mutation burden(TMB) and survival.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13663 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13663-e13663

Author(s):

Ke Li ◽

Xi Guo ◽

Yunhua Mao ◽

Mengmei Yang ◽

Mengli Huang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Molecular Subtype ◽

Prostate Adenocarcinoma ◽

Chinese Patients ◽

Cyclin Dependent Kinase ◽

Poor Prognostic Factor ◽

Cancer Types ◽

Chinese Cancer Patients ◽

Pan Cancer

e13663 Background: Cyclin-dependent kinase 12 (CDK12) is a cyclin-dependent kinase that regulates transcription and RNA splicing, thereby modulating multiple cellular processes. It has been suggested that CDK12 loss-of-function mutations lead to a higher neoantigen burden and favorable responses to PD-1 inhibitors in advanced prostate cancer. Given this potentially actionable molecular subtype, we sought to determine the prevalence of CDK12 alterations in Chinese cancer patients and the association with TMB and overall survival(OS). Methods: The prevalence of CDK12 alterations were queried in 3D Medicines database with 15,745 Chinese cancer patients involved. Whole-exome sequencing data of 464 patients with prostate adenocarcinoma(PRAD) from the Cancer Genome Altas (TCGA) were downloaded to explore the association between CDK12 gene alteration and OS. And the association with TMB were analyzed in a cohort of 731 patients with various cancer types published by Memorial Sloan Kettering (MSKCC) (Samstein et al., Nature Genetics, 2019). Results: Any CDK12 and known or likely deleterious CDK12 mutations were identified in 598(3.8%) and 98(0.62%) patients, respectively. Across all cancer types, prostate adenocarcinoma(PRAD) was found to have the highest frequency of deleterious mutations(8.75%, 23/263), followed by breast cancer (4.97%, 25/503). Mutations were also detected in multiple cancer types including bladder cancer, ovarian cancer, lung cancer, colorectal cancer and so on with a frequency of less than 1%. CDK12 mutations were associated with shorter OS (HR = 15.25; 95% CI, 2.88-80.73; p < 0.001) in TCGA PRAD and cholangiocarcinoma datasets, which was not seen in other cancer types. Patients harboring CDK12 mutation had a significant higher TMB(p < 0.001) in the pan-cancer study of publicly-available cohort from MSKCC. Conclusions: CDK12 alterations existed across tumor types in Chinese patients with relatively high frequencies detected in PRAD and breast cancer and represent extremely rare events in multiple cancers. CDK12 mutation was a poor prognostic factor in PRAD and cholangiocarcinoma. In a pan cancer analysis patients with CDK12 mutation tended to have a significant higher TMB and may benefit from PD-1/L1 blockade immunotherapy.

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A Pan-cancer Analysis of the Prognostic and Immunological Role of PPP1R14A

10.21203/rs.3.rs-882685/v1 ◽

2021 ◽

Author(s):

JiaJie Lu ◽

Rihong Huang ◽

Haojian Wang ◽

Yuecheng Peng ◽

Yongyang Fan ◽

...

Keyword(s):

Survival Analysis ◽

Cancer Patients ◽

Immune Checkpoint ◽

Cancer Survival ◽

Malignant Tumors ◽

Genetic Alterations ◽

Poor Overall Survival ◽

Carcinogenic Effect ◽

Genetic Changes ◽

Pan Cancer

Abstract BackgroundDespite emerging evidence revealed the remarkable roles of Protein Phosphatase 1 Regulatory Inhibitor Subunit 14A (PPP1R14A) in cancer tumorigenesis and progression, no pan-cancer analysis is available. Our research, for the first time, comprehensively investigated the potential carcinogenic mechanism of PPP1R14A across 33 tumors using bioinformatic techniques. MethodsTCGA datasets and the CPTAC datasets embedded in UALCAN were first applied to study the differential expression of PPP1R14A in various cancer types at the transcription and protein levels, respectively. Besides, we also conducted relevant prognostic survival analysis and used the GEPIA2 database to explore the association between PPP1R14A expression and pathological stages. In addition, cBioPortal and UALCAN databases were employed to analyze the genetic alterations and post-transcriptional phosphorylation of PPP1R14A. Then based on TCGA, we analyzed the relationship between PPP1R14A and immune infiltration, the correlation with tumor mutational burden (TMB), microsatellite instability (MSI) and immune checkpoint molecules (ICMs), and whether it is expected to be a predictive indicator in cancer patients, which was achieved by receiver operating characteristic (ROC) curve. Finally, STRING, GEPIE2 and TIMER2.0 databased were used to explore the potential mechanism of PPP1R14A in cancer and find molecules that have potential close interactions with PPP1R14A.ResultsPPP1R14A is down-expressed in major malignancies and there is a significant correlation between the PPP1R14A expression and the prognosis of patients. Pan-cancer survival analysis indicated that the high expression of PPP1R14A in most cases was associated with poor overall survival (OS), disease-specific survival (DSS), and progress-free interval (PFI) across patients with various malignant tumors, containing adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA). The results of ROC analysis subsequently exhibited that the molecule has a high reference significance in diagnosing a variety of cancers. Besides, we detected that the frequency of PPP1R14A genetic changes including genetic mutations and copy number alterations (CNAs) in uterine carcinosarcoma reached 16.07%, and these alterations brought misfortune to the survival and prognosis of cancer patients. In addition, the methylation within the promoter region of PPP1R14A DNA was enhanced in a majority of cancers. Downregulated phosphorylation levels of phosphorylation sites including S26, T38, etc. in most cases took place in several tumors, such as breast cancer, colon cancer, etc. PPP1R14A remarkably correlated with the levels of infiltrating cells and immune checkpoint genes. ConclusionsOur research summarized and analyzed the carcinogenic effect of PPP1R14A in different tumors comprehensively and provided a theoretical basis for promising therapeutic and immunotherapy strategies.

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USH2A Mutation is Associated With Tumor Mutation Burden and Antitumor Immunity in Patients With Colon Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.762160 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuanyuan Sun ◽

Long Li ◽

Wenchao Yao ◽

Xuxu Liu ◽

Yang Yang ◽

...

Keyword(s):

Immune Response ◽

Immune Checkpoint ◽

Antitumor Immunity ◽

Gene Mutations ◽

Colon Adenocarcinoma ◽

Cancer Genome ◽

Gene Set Enrichment Analysis ◽

Cox Analysis ◽

Immune Score ◽

Differential Genes

Colon adenocarcinoma (COAD) is one of the diseases with the highest morbidity and mortality in the world. At present, immunotherapy has become a valuable method for the treatment of COAD. Tumor mutational burden (TMB) is considered to be the most common biomarker for predicting immunotherapy. According to reports, the mutation rate of COAD ranks third. However, whether these gene mutations are related to TMB and immune response is still unknown. Here, COAD somatic mutation data were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Bioinformatics methods were used to study the relationships among gene mutations, COAD survival prognosis, and tumor immune response. A total of 22 of the top 40 mutations in TCGA and ICGC databases were the same. Among them, the USH2A mutation was associated with high TMB and poor clinical prognosis. According to Gene Set Enrichment Analysis (GSEA) and the CIBERSORT algorithm, we determined that the USH2A mutation upregulates signaling pathways involved in the immune system and the antitumor immune response. In cases with a USH2A mutation, the immune score and MSI score of TCGA samples increased, the expression of immune checkpoint genes decreased significantly, and the TIDE score decreased significantly. Dependent on the presence or absence of a USH2A mutation, TCGA COAD samples were analyzed for differentially expressed genes, 522 of which were identified. Using a univariate Cox analysis and LASSO COX analysis of these differential genes, a prediction model was established, which established significant differences in the infiltration of immune cells, immune checkpoint gene expression, immune score, MSI score, TMB, and TIDE in patients in high- and low-risk groups. In conclusion, mutation of USH2A is frequent in COAD and is related to an increase in TMB and the antitumor immunity. The differential genes screened by USH2A mutation allowed the construction of a risk model for predicting the survival and prognosis of cancer patients, in addition to providing new ideas for COAD immunotherapy.

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