Immune classification and identification of prognostic genes for uveal melanoma based on six immune cell signatures

AbstractCutaneous melanoma could be treated by immunotherapy, which only has limited efficacy on uveal melanoma (UM). UM immunotyping for predicting immunotherapeutic responses and guiding immunotherapy should be better understood. This study identified molecular subtypes and key genetic markers associated with immunotherapy through immunosignature analysis. We screened a 6-immune cell signature simultaneously correlated with UM prognosis. Three immune subtypes (IS) were determined based on the 6-immune cell signature. Overall survival (OS) of IS3 was the longest. Significant differences of linear discriminant analysis (LDA) score were detected among the three IS types. IS3 with the highest LDA score showed a low immunosuppression. IS1 with the lowest LDA score was more immunosuppressive. LDA score was significantly negatively correlated with most immune checkpoint-related genes, and could reflect UM patients’ response to anti-PD1 immunotherapy. Weighted correlation network analysis (WGCNA) identified that salmon, purple, yellow modules were related to IS and screened 6 prognostic genes. Patients with high-expressed NME1 and TMEM255A developed poor prognosis, while those with high-expressed BEX5 and ROPN1 had better prognosis. There was no notable difference in OS between patients with high-expressed LRRN1 and ST13 and those with low-expressed LRRN1 and ST13. NME1, TMEM255A, Bex5 and ROPN1 showed potential prognostic significance in UM.

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Prognostic Significance and Immune Infiltration of Microenvironment‐related Signatures in Pancreatic Cancer

10.21203/rs.3.rs-60885/v1 ◽

2020 ◽

Author(s):

Qian Lu ◽

Yu Zhang ◽

Weihong Gu ◽

Xinrong Ji ◽

Zhong Chen

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Immune Cell ◽

Differential Expression Analysis ◽

Prognostic Significance ◽

Ductal Adenocarcinoma ◽

Immune Infiltration ◽

Protein Protein Interaction ◽

Tumor Tissues ◽

Cox Analysis

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the highly fatal and most aggressive types of malignancies and accounts for the vast majority of Pancreatic Cancer (PC). Numerous studies have reported that the tumor microenvironment (TME) was significantly correlated with the oncogenesis, progress, and prognosis of various malignancies. Therefore, mining of TME-related genes is reasonably important to improve the overall survival (OS) of patients with PDAC. Methods: The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm was applied to identify differential expressed genes (DEGs). Functional and pathway enrichment analyses, protein–protein interaction (PPI) network construction and module analysis, overall survival analysis and tumor immune estimation resource (TIMER) database analysis were then performed on DEGs. Results: Data analysis indicated that higher immune scores were correlated with better overall survival (P = 0.033). Differential expression analysis obtained 90 intersection genes influencing both stromal and immune scores. Among these intersection genes, CA9, EBI3, SPOCK2, WDFY4, CD1D and CCL22 were significantly correlated with OS in PDAC patients. Moreover, multivariate Cox analysis revealed that CA9, SPOCK2 and CD1D were the most significant prognostic genes, and were closely correlated with immune infiltration in TCGA cohort. Further analysis indicated that CD1D were significantly related with immune cell biomarkers for PDAC patients. Conclusions: In summary, our findings provide a more comprehensive insight into TME and show a list of prognostic immune associated genes in PDAC. However, further studies on these genes need to be performed to gain additional understanding of the association between TME and prognosis in PDAC.

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Incidence and Prognostic significance of Signet Ring Cell Histology in Gastric Cancer. A cross sectional study from Turkey: Pure Signet Ring Cell Histology in Gastric Cancer

10.32592/ircmj.2020.22.9.34 ◽

2020 ◽

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Poor Prognosis ◽

Prognostic Significance ◽

Good Prognosis ◽

Signet Ring Cell ◽

Stage I ◽

Stage Iii ◽

Signet Ring ◽

Ring Cell

Purpose: The present study aims to evaluate the incidence of signet ring cell (SRC) histology in patients with gastric cancer and its prognostic significance on the disease stage. Methods: Between November 2006 and September 2019, 309 patients were reviewed retrospectively in Kartal Koşuyolu High Specialization Training and Research Hospital Gastroenterology Surgery clinic in Turkey and the clinicopathological features and survival status were examined in the presence of ring cell histology. Results: Of the patients, 71.4% had gastric cancer with a non-SRC histology and 28.6% had an SRC histology. The presence of an SRC histology was found to be associated with young age (p=0.007), advanced depth of wall invasion (p=0.001), number of positive lymph nodes (p=0.022) and presence of vascular invasion (p=0.044). The presence of an SRC histology was associated with good prognosis in patients with stage I gastric cancer (p=0.045), but with poor prognosis in patients with stage III disease (p=0.034). The study found no significant association between stage II disease and overall survival. Conclusions: The present study found survival to be associated with good prognosis in stage I, and poor prognosis in stage III among patients with gastric cancer with SRC histology. No prognostic significance could be established for overall survival.

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Prognostic Significance of Gene Signature of Tertiary Lymphoid Structures in Patients With Lung Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.693234 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hong Feng ◽

Fujun Yang ◽

Lihong Qiao ◽

Kai Zhou ◽

Junfei Wang ◽

...

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Immune Cell ◽

Prognostic Significance ◽

Gene Signature ◽

Driver Gene ◽

Immune Microenvironment ◽

High Group ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

BackgroundLung adenocarcinoma (LUAD) is a highly mortal cancer. Tertiary lymphoid structures (TLS) are ectopic lymphoid organs with similar morphological and molecular characters to secondary lymphoid organ. The aim of this study is to investigate the prognostic effect of a gene signature associated with TLSs, including B-cell-specific genes.MethodsClinical data of 515 LUAD patients in the TGCA cohort were used to examine the relationship of TLS signature with immune microenvironment, tumor mutational burden (TMB), and driver gene mutations. Patients were divided into the TLS signature high group and TLS signature low group, and comparative analysis of survival and its influencing factors between the two groups was performed. The resulting data were then validated in the GSE37745 cohort.ResultsTLS signature high group had significantly better overall survival (OS) and progression-free interval (PFI) as well as significantly higher infiltration of immune cell subsets, cancer immune cycle (CIC) signature except for immunogram score2 (IGS2), and expression of major checkpoint genes than the TLS signature low group. Notably, while TLS signature was not markedly associated with TMB and mutation frequencies of driver genes, there were significant differences in overall survival of patients with given mutation status of EGFR, KRAS, BRAF and TP53 genes between the TLS signature high and low groups.ConclusionThis study provided evidence that LUAD patients with high TLS signature had a favorable immune microenvironment and better prognosis, suggesting that TLS signature is an independent positive prognostic factor for LUAD patients.

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Identification and Validation of Immune Molecular Subtypes in Pancreatic Ductal Adenocarcinoma: Implications for Prognosis and Immunotherapy

Frontiers in Immunology ◽

10.3389/fimmu.2021.690056 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ruiyu Li ◽

Yangzhige He ◽

Hui Zhang ◽

Jing Wang ◽

Xiaoding Liu ◽

...

Keyword(s):

Overall Survival ◽

Prognostic Factor ◽

Pancreatic Ductal Adenocarcinoma ◽

Immune Cell ◽

Molecular Subtypes ◽

Molecular Subtype ◽

The Cancer Genome Atlas ◽

Ductal Adenocarcinoma ◽

Expression Data ◽

Favorable Prognostic Factor

BackgroundPancreatic ductal adenocarcinoma (PDAC) remains treatment refractory. Immunotherapy has achieved success in the treatment of multiple malignancies. However, the efficacy of immunotherapy in PDAC is limited by a lack of promising biomarkers. In this research, we aimed to identify robust immune molecular subtypes of PDAC to facilitate prognosis prediction and patient selection for immunotherapy.MethodsA training cohort of 149 PDAC samples from The Cancer Genome Atlas (TCGA) with mRNA expression data was analyzed. By means of non-negative matrix factorization (NMF), we virtually dissected the immune-related signals from bulk gene expression data. Detailed immunogenomic and survival analyses of the immune molecular subtypes were conducted to determine their biological and clinical relevance. Validation was performed in five independent datasets on a total of 615 samples.ResultsApproximately 31% of PDAC samples (46/149) had higher immune cell infiltration, more active immune cytolytic activity, higher activation of the interferon pathway, a higher tumor mutational burden (TMB), and fewer copy number alterations (CNAs) than the other samples (all P < 0.001). This new molecular subtype was named Immune Class, which served as an independent favorable prognostic factor for overall survival (hazard ratio, 0.56; 95% confidence interval, 0.33-0.97). Immune Class in cooperation with previously reported tumor and stroma classifications had a cumulative effect on PDAC prognostic stratification. Moreover, programmed cell death-1 (PD-1) inhibitors showed potential efficacy for Immune Class (P = 0.04). The robustness of our immune molecular subtypes was further verified in the validation cohort.ConclusionsBy capturing immune-related signals in the PDAC tumor microenvironment, we reveal a novel molecular subtype, Immune Class. Immune Class serves as an independent favorable prognostic factor for overall survival in PDAC patients.

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Prognostic Significance of mRNA Expression RBBP8 or its Methylation in Gliomas

10.21203/rs.3.rs-713313/v1 ◽

2021 ◽

Author(s):

Zhengdong Liu ◽

Xingbo Cheng ◽

Yanzheng Gao ◽

Zhibin Han ◽

Shaochong Lin ◽

...

Keyword(s):

Poor Prognosis ◽

Immune Cell ◽

Cox Regression ◽

Prognostic Significance ◽

Gene Set Enrichment Analysis ◽

Immune Checkpoints ◽

Low Grade ◽

Risk Indicator ◽

Carcinogenic Effect ◽

Who Grade

Abstract Retinoblastoma-binding protein 8 (RBBP8) affects the prognosis of patients with malignancies through various mechanisms. However, its function in gliomas is unknown. Our study explored the effects of RBBP8 on the prognosis of glioma patients, as well as its regulatory role in the glioma immune microenvironment. We used various bioinformatics methods to analyze the transcriptional profiles and methylation data of RBBP8 in gliomas from multiple databases. Our results showed that the mRNA and protein expression of RBBP8 in gliomas was higher than that in normal tissues and positively correlated with malignant clinical features such as age and WHO grade. A Kaplan–Meier analysis showed that patients with high RBBP8 expression had a poor prognosis. Cox regression demonstrated that RBBP8 was an independent risk indicator and had good diagnostic value for the poor prognosis of glioma. A meta-analysis confirmed the carcinogenic effect of RBBP8 on glioma, while the Tumor Immune Estimation Resource analysis showed that RBBP8 was positively correlated with the infiltration of six immune cell types in low-grade glioma, but only with dendritic cells in glioblastoma multiforme. Importantly, RBBP8 was positively correlated with many well-known immune checkpoints (e.g., CTLA4 and PDL-1). Finally, a gene set enrichment analysis revealed that RBBP8 can promote the activation of cancer-related pathways such as cell cycle, DNA replication and so on. In conclusion, this study is the first to elaborate on the value of RBBP8 in the pathological process of glioma for anti-tumor immunotherapy. In addition, the expression of RBBP8 and its methylation site, cg05513509, may provide potential targets for glioma therapy.

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Copy number analysis to identify tumor suppressor genes associated with enzalutamide (Enza) resistance and poor prognosis in metastatic castration-resistant prostate cancer (mCRPC) patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5011 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5011-5011

Author(s):

Xiangnan Guan ◽

Duan-Chen Sun ◽

Eric Lu ◽

Joshua A. Urrutia ◽

Robert Evan Reiter ◽

...

Keyword(s):

Overall Survival ◽

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Copy Number ◽

Poor Prognosis ◽

Molecular Mechanisms ◽

Prognostic Significance ◽

Copy Number Loss ◽

Castration Resistant Prostate Cancer ◽

Suppressor Genes

5011 Background: Although enza prolongs life in mCRPC pts, the development of drug resistance and subsequent disease progression is nearly universal. Seeking to clarify molecular mechanisms that underlie enza resistance, we analyzed whole genome sequencing (WGS) and RNA sequencing (seq) of tumors obtained from patients with enza-naive or -resistant mCRPC. Methods: One hundred and one men with mCRPC who underwent image-guided biopsy and subsequent WGS were included (n = 64 with enza-naive and n = 37 with enza-resistant mCRPC). The differential copy number alteration (CNA) events enriched in enza-resistant vs. naïve samples were determined, and the prognostic significance of differential CNAs was assessed. RNA-seq data were evaluated to confirm that CNAs correlated with changes in gene expression of relevant loci and to identify potentially druggable targets selectively activated in tumors with specific CNAs. Results: Copy number loss was more common than gain in enza-resistant tumors. Specifically, we identified 123 protein-coding genes that were more commonly lost in enza-resistant samples—eight of which were previously described tumor suppressor genes. There was a strong concordance of copy number loss and reduced mRNA expression of these genes. We identified one gene from this list of eight genes whose copy number loss was associated with poor overall survival (median overall survival from date of CRPC was 19.1 months in tumors with gene loss vs. 42.0 months in intact tumors, hazard ratio 3.8 [1.46–9.8], log-rank p = 0.003). Finally, Master Regulator analysis determined that tumors with copy number loss of this poor prognosis gene had activation of several potentially targetable factors, including the kinases Akt and PLK1. Conclusions: Copy number loss of specific tumor suppressor genes is associated with enza resistance in mCRPC patients. Previously unappreciated molecular subsets of enza-resistant CRPC were identified, including one subset associated with poor clinical outcome.

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Reduced integrin alpha3 expression as a factor of poor prognosis of patients with adenocarcinoma of the lung.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.3.1060 ◽

1998 ◽

Vol 16 (3) ◽

pp. 1060-1067 ◽

Cited By ~ 49

Author(s):

M Adachi ◽

T Taki ◽

C Huang ◽

M Higashiyama ◽

O Doi ◽

...

Keyword(s):

Gene Expression ◽

Lung Cancer ◽

Overall Survival ◽

Survival Rate ◽

Poor Prognosis ◽

Prognostic Significance ◽

Lymph Node Status ◽

Overall Survival Rate ◽

Rt Pcr ◽

Integrin Alpha3

PURPOSE We investigated the possible association between integrin alpha3 and motility-related protein (MRP-1), cluster of differentiation antigen 9 (CD9) gene expression in non-small-cell lung cancer (NSCLC) and evaluated the prognostic significance of integrin alpha3 expression. PATIENTS AND METHODS We performed a retrospective study of integrin alpha3 and MRP-1/CD9 expression in resected tumor tissues from 151 NSCLC patients using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS The ratio of integrin alpha3/beta-actin expression ranged from 0 to 5.87 (mean was 0.80; median, 0.70). Using the cutoff value of 0.7, there were 78 (52%) integrin alpha3-positive tumors and 73 (48%) tumors with reduced integrin alpha3 expression. The immunohistochemical results agreed well with those of the RT-PCR assays, and 88% had no discrepancy. In case of discrepancy, the results of RT-PCR were used in specimen classification. Integrin alpha3 gene expression was independent from MRP-1/CD9 gene expression. No significant association was found between integrin alpha3 expression and the patients' clinical characteristics. The overall survival rate of patients with integrin alpha3-positive NSCLCs was only slightly better than that of individuals whose tumors had reduced integrin alpha3 expression (55.9% v 47.1%; P = .085). By comparison, the overall survival rate of patients with integrin alpha3-positive adenocarcinomas was strikingly greater than in those whose tumors had reduced gene expression (54.4% v 35.2%; P = .004). Multivariate analysis with the Cox regression model of NSCLC and adenocarcinoma indicated that integrin alpha3 expression correlated better (P = .0188 and P = .0008, respectively) with the overall survival rate than other variables, except lymph node status. CONCLUSION No significant association was found between integrin alpha3 and MRP-1/CD9 gene expression in lung cancer. However, reduced integrin alpha3 expression is a poor prognosis factor in patients with adenocarcinomas.

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A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis

Clinical Sarcoma Research ◽

10.1186/s13569-019-0122-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 8

Author(s):

Nam Q. Bui ◽

Joanna Przybyl ◽

Sally E. Trabucco ◽

Garrett Frampton ◽

Trevor Hastie ◽

...

Keyword(s):

Overall Survival ◽

Soft Tissue ◽

Poor Prognosis ◽

Prognostic Significance ◽

Genomic Analysis ◽

Bone Sarcoma ◽

The Cancer Genome Atlas ◽

Peripheral Nerve Sheath Tumors ◽

Cdkn2a Deletion ◽

Tcga Dataset

Abstract Background Sarcomas are a rare, heterogeneous group of tumors with variable tendencies for aggressive behavior. Molecular markers for prognosis are needed to risk stratify patients and identify those who might benefit from more intensive therapeutic strategies. Patients and methods We analyzed somatic tumor genomic profiles and clinical outcomes of 152 soft tissue (STS) and bone sarcoma (BS) patients sequenced at Stanford Cancer Institute as well as 206 STS patients from The Cancer Genome Atlas. Genomic profiles of 7733 STS from the Foundation Medicine database were used to assess the frequency of CDKN2A alterations in histological subtypes of sarcoma. Results Compared to all other tumor types, sarcomas were found to carry the highest relative percentage of gene amplifications/deletions/fusions and the lowest average mutation count. The most commonly altered genes in STS were TP53 (47%), CDKN2A (22%), RB1 (22%), NF1 (11%), and ATRX (11%). When all genomic alterations were tested for prognostic significance in the specific Stanford cohort of localized STS, only CDKN2A alterations correlated significantly with prognosis, with a hazard ratio (HR) of 2.83 for overall survival (p = 0.017). These findings were validated in the TCGA dataset where CDKN2A altered patients had significantly worse overall survival with a HR of 2.7 (p = 0.002). Analysis of 7733 STS patients from Foundation One showed high prevalence of CDKN2A alterations in malignant peripheral nerve sheath tumors, myxofibrosarcomas, and undifferentiated pleomorphic sarcomas. Conclusion Our clinico-genomic profiling of STS shows that CDKN2A deletion was the most prevalent DNA copy number aberration and was associated with poor prognosis.

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Association of JMJD2B and Hypoxia-Inducible Factor 1 Expressions with Poor Prognosis in Osteosarcoma

Analytical Cellular Pathology ◽

10.1155/2020/2563208 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Xujian Liu ◽

Qianqian Zhang ◽

Yi Zhao ◽

Jianjun Xun ◽

Hongzeng Wu ◽

...

Keyword(s):

Overall Survival ◽

Poor Prognosis ◽

Clinical Characteristics ◽

Malignant Tumors ◽

Univariate Analysis ◽

Hypoxia Inducible Factor ◽

Prognostic Significance ◽

Expression Levels ◽

Hypoxia Inducible Factor 1 ◽

Enneking Stage

Background. JMJD2B has been reported to be implicated in malignant tumors. This study is aimed at exploring the expression and prognostic significance of JMJD2B in osteosarcoma and its association with hypoxia-inducible factor 1 (HIF1). Methods. The histopathological and clinical characteristics were retrospectively reviewed from 53 osteosarcoma patients. JMJD2B and HIF1 were examined by immunohistochemical staining of paraffin-embedded osteosarcoma samples, and their association with clinical characteristics was examined by Spearman’s test. Overall survival was examined by Kaplan-Meier analysis, and prognostic factors were identified by univariate and multivariate regression analyses. Results. JMJD2B and HIF1 expression levels were both significantly associated with Enneking stage, distant metastasis, and neoadjuvant chemotherapy, and the JMJD2B and HIF1 expressions were positively correlated (p<0.001, R=0.752). In addition, univariate analysis showed that the expression of both JMJD2B and HIF1 was significantly associated with overall survival, but multivariate analysis showed that only JMJD2B expression was significantly associated with overall survival in osteosarcoma patients. Conclusions. JMJD2B and HIF1 expression levels show significant correlation with osteosarcoma progression, and JMJD2B could predict poor prognosis of osteosarcoma patients.

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Identification of Immune Cell Infiltration Landscape and Their Prognostic Significance in Uveal Melanoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.713569 ◽

2021 ◽

Vol 9 ◽

Author(s):

Han Zhao ◽

Yun Chen ◽

Peijun Shen ◽

Lan Gong

Keyword(s):

Gene Expression ◽

Uveal Melanoma ◽

Immune Cell ◽

Prognostic Significance ◽

Principal Component ◽

Clinical Information ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Cell Infiltration ◽

Immune Cell Infiltration

Uveal melanoma (UVM) is the most common primary intraocular cancer in adults. Increasing evidence has demonstrated that immune cell infiltration (ICI) is crucial in predicting patient outcomes and therapeutic efficacy. Thus, describing the immune cell infiltrative landscape of UVM tumors may yield a novel prognostic marker and provide direction for immunotherapeutic selection. In this study, the gene expression data and clinical information of UVM patients were obtained from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. The ICI landscape of UVM was analyzed using the CIBERSORT and ESTIMATE algorithms. Two ICI phenotypes were defined, and the ICI scores were calculated by using principal component analysis algorithms. We found that a subtype with high ICI scores had poorer prognosis and increased expression levels of immune checkpoint-related genes. This study demonstrates that ICI scores are an independent prognostic biomarker and highlights their value in predicting immunotherapeutic outcomes.

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