scholarly journals Quantitative Assessment and Prognostic Associations of the Immune Landscape in Ovarian Clear Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3854
Author(s):  
Saira Khalique ◽  
Sarah Nash ◽  
David Mansfield ◽  
Julian Wampfler ◽  
Ayoma Attygale ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Spatial Distribution ◽  
Cell Carcinoma ◽  
Immune Cell ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Cell Populations ◽  
Ovarian Clear Cell Carcinoma ◽  
Risk Patients

Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian cancer characterised by a high frequency of loss-of-function ARID1A mutations and a poor response to chemotherapy. Despite their generally low mutational burden, an intratumoural T cell response has been reported in a subset of OCCC, with ARID1A purported to be a biomarker for the response to the immune checkpoint blockade independent of micro-satellite instability (MSI). However, assessment of the different immune cell types and spatial distribution specifically within OCCC patients has not been described to date. Here, we characterised the immune landscape of OCCC by profiling a cohort of 33 microsatellite stable OCCCs at the genomic, gene expression and histological level using targeted sequencing, gene expression profiling using the NanoString targeted immune panel, and multiplex immunofluorescence to assess the spatial distribution and abundance of immune cell populations at the protein level. Analysis of these tumours and subsequent independent validation identified an immune-related gene expression signature associated with risk of recurrence of OCCC. Whilst histological quantification of tumour-infiltrating lymphocytes (TIL, Salgado scoring) showed no association with the risk of recurrence or ARID1A mutational status, the characterisation of TILs via multiplexed immunofluorescence identified spatial differences in immunosuppressive cell populations in OCCC. Tumour-associated macrophages (TAM) and regulatory T cells were excluded from the vicinity of tumour cells in low-risk patients, suggesting that high-risk patients have a more immunosuppressive microenvironment. We also found that TAMs and cytotoxic T cells were also excluded from the vicinity of tumour cells in ARID1A-mutated OCCCs compared to ARID1A wild-type tumours, suggesting that the exclusion of these immune effectors could determine the host response of ARID1A-mutant OCCCs to therapy. Overall, our study has provided new insights into the immune landscape and prognostic associations in OCCC and suggest that tailored immunotherapeutic approaches may be warranted for different subgroups of OCCC patients.

Integrative genomic and transcriptomic analysis reveals prognostic markers and immune subtype in Chinese ovarian clear cell carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17529-e17529
Author(s):  
Huijuan Yang ◽  
Shuang Ye ◽  
Qin Li ◽  
Yutuan Wu ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Carcinoma ◽  
Prognostic Markers ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Genetic Alterations ◽  
Transcriptomic Analysis ◽  
Clinical Factors ◽  
Ovarian Clear Cell Carcinoma ◽  
Poor Survival

e17529 Background: Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer characterized by chemo-resistance and poor survival. Herein, we performed comprehensive genomic and transcriptomic profiling of OCCC tissues to identify prognostic markers and immune subtype in Chinese patients. Methods: A total of 61 patients were included, comprising 41 early-stage and 19 late-stage tumors. Tissue samples were collected before chemotherapy and subjected to capture-based targeted sequencing using a panel consisting of 520 cancer related genes and whole transcriptomic sequencing. Genetic alterations, tumor mutation burden (TMB), microsatellite instability (MSI), and gene expression were evaluated. Association analysis was performed to evaluate clinical and genetic factors with platinum-sensitivity and treatment effects. A nomogram was constructed to predict survival outcomes. Single sample Gene Set Enrichment analysis (ssGSEA) was performed with gene expression profile and immune gene sets. Results: Genetic alterations were mainly identified in ARID1A (49%), PIK3CA (48%), TP53 (18%), ATM (15%), SMARCA4 (13%) and PRKDC (13%). Co-occurrence of mutations in ARID1A with PIK3CA and PRKDC were observed (p < 0.05). Meanwhile, no alterations were identified in BRCA1/2. Patients harboring ATM mutations tended to be platinum sensitive compared to those wildtype counterparts (p < 0.05). In patients with stage IV OCCC, mutations of ARID1A, PIK3CA, SMARCA4 and the HRR pathway were also related to higher percentage of platinum-sensitivity, though significance was not achieved. Mutations of FGFR2, NOTCH1 and the BER pathway were more frequently identified in patients with stage II to IV than stage I (p < 0.05). Patients harboring alterations at chromosome 8q covering genes such as PRKDC showed better overall survival (OS) (p < 0.05). Both clinical factors and frequently mutated genes were used to construct a nomogram for progression-free survival (PFS) prediction. The clinical factors (stage, platinum response and residual disease) in combination with genetic mutations ( ATM and SMARCA4) showed better performance in predicting PFS than clinical factors alone (concordance index 0.85 vs. 0.74, p < 0.01). Transcriptomic analysis with ssGSEA of immune pathway revealed an immune subtype with enrichment of PD-1 signaling. OCCC patients with this immune subtype showed poor PFS and OS. Integration of genomic and transcriptomic analysis showed that the immune subtype patients had higher mutation rate of PIK3CA. Conclusions: The mutational profiles of OCCC were varied in patients with different platinum response and tumor stages. An immune subtype of OCCC with poor survival and enrichment of PD-1 signaling was identified. Our study identified several potential prognostic markers of OCCC at genetic level and revealed an immune subtype for potential immunotherapy.

scholarly journals Suppression of ARID1A associated with decreased CD8 T cells improves cell survival of ovarian clear cell carcinoma

2021 ◽  
Vol 32 (1) ◽  
Author(s):  
Un Suk Jung ◽  
Kyueng-Whan Min ◽  
Dong-Hoon Kim ◽  
Mi Jung Kwon ◽  
HoHyun Park ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Survival ◽  
Cell Carcinoma ◽  
Cd8 T Cells ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Ovarian Clear Cell Carcinoma

scholarly journals Using Genomic and Transcriptome Analyses to Identify the Role of the Oxidative Stress Pathway in Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance

2021 ◽  
Vol 2021 ◽  
pp. 1-38
Author(s):  
Xiangyu Che ◽  
Xiaochen Qi ◽  
Yingkun Xu ◽  
Qifei Wang ◽  
Guangzhen Wu
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Free Radicals ◽  
Cell Carcinoma ◽  
Immune Cell ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Renal Clear Cell Carcinoma ◽  
The Body ◽  
Prognosis Model

Oxidative stress (OS) refers to endogenous and/or exogenous stimulation when the balance between oxidation and antioxidants in the body is disrupted, resulting in excessive production of free radicals. Excessive free radicals exert a series of negative effects on the body, which can result in the oxidation of and infliction of damage on biological molecules and further cause cell death and tissue damage, which are related to many pathological processes. Pathways related to OS have always been the focus of medical research. Several studies are being conducted to develop strategies to treat cancer by exploring the OS pathways. Therefore, this study is aimed at determining the correlation between the OS pathway and kidney renal clear cell carcinoma (KIRC) through bioinformatics analysis, at proving the effect of common anticancer drugs on the OS pathway, and at constructing a prognosis model of patients with KIRC based on several genes with the strongest correlation between the OS pathway and KIRC. We first collected and analyzed gene expression and clinical information of related patients through TCGA database. Then, we divided the samples into three clusters according to their gene expression levels obtained through cluster analysis. Using these three clusters, we performed GDSC drug analysis and GSEA analysis and examined the correlation among the OS pathway, histone modification, and immune cell infiltration. We also analyzed the response of anti-PD-1 and anti-CTLA-4 to the OS pathway. Thereafter, we used LASSO regression to select the most suitable nine genes, combined with the clinicopathological characteristics to establish the prognosis model of patients with KIRC, and verified the scientific precision of the model. Finally, tumor mutational burden was calculated to verify whether patients would benefit from immunotherapy. The results of this study may provide a reference for the establishment of treatment strategies for patients with KIRC.

scholarly journals Cytokine gene expression signature in ovarian clear cell carcinoma

2012 ◽  
Vol 41 (3) ◽  
pp. 1094-1100 ◽  
Author(s):  
NOZOMU YANAIHARA ◽  
MICHAEL S. ANGLESIO ◽  
KAZUNORI OCHIAI ◽  
YUKIHIRO HIRATA ◽  
MISATO SAITO ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Carcinoma ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Gene Expression Signature ◽  
Cytokine Gene Expression ◽  
Cytokine Gene ◽  
Ovarian Clear Cell Carcinoma ◽  
Expression Signature

scholarly journals MicroRNA Gene Expression Signature Driven by miR-9 Overexpression in Ovarian Clear Cell Carcinoma

PLoS ONE ◽  
2016 ◽  
Vol 11 (9) ◽  
pp. e0162584 ◽  
Author(s):  
Nozomu Yanaihara ◽  
Yukiko Noguchi ◽  
Misato Saito ◽  
Masataka Takenaka ◽  
Satoshi Takakura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Carcinoma ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Gene Expression Signature ◽  
Ovarian Clear Cell Carcinoma ◽  
Expression Signature ◽  
Microrna Gene

scholarly journals The Potential Role of Complement System in the Progression of Ovarian Clear Cell Carcinoma Inferred from the Gene Ontology-Based Immunofunctionome Analysis

2020 ◽  
Vol 21 (8) ◽  
pp. 2824 ◽  
Author(s):  
Kuo-Min Su ◽  
Tzu-Wei Lin ◽  
Li-Chun Liu ◽  
Yi-Pin Yang ◽  
Mong-Lien Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Ontology ◽  
Cell Carcinoma ◽  
Complement System ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Expression Profiles ◽  
Alternative Pathway ◽  
Ovarian Clear Cell Carcinoma ◽  
C5a Receptor

Ovarian clear cell carcinoma (OCCC) is the second most common epithelial ovarian carcinoma (EOC). It is refractory to chemotherapy with a worse prognosis after the preliminary optimal debulking operation, such that the treatment of OCCC remains a challenge. OCCC is believed to evolve from endometriosis, a chronic immune/inflammation-related disease, so that immunotherapy may be a potential alternative treatment. Here, gene set-based analysis was used to investigate the immunofunctionomes of OCCC in early and advanced stages. Quantified biological functions defined by 5917 Gene Ontology (GO) terms downloaded from the Gene Expression Omnibus (GEO) database were used. DNA microarray gene expression profiles were used to convert 85 OCCCs and 136 normal controls into to the functionome. Relevant offspring were as extracted and the immunofunctionomes were rebuilt at different stages by machine learning. Several dysregulated pathogenic functions were found to coexist in the immunopathogenesis of early and advanced OCCC, wherein the complement-activation-alternative-pathway may be the headmost dysfunctional immunological pathway in duality for carcinogenesis at all OCCC stages. Several immunological genes involved in the complement system had dual influences on patients’ survival, and immunohistochemistrical analysis implied the higher expression of C3a receptor (C3aR) and C5a receptor (C5aR) levels in OCCC than in controls.

scholarly journals Antioxidant Gene Signature Impacts the Immune Infiltration and Predicts the Prognosis of Kidney Renal Clear Cell Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Xueting Ren ◽  
Li Ma ◽  
Nan Wang ◽  
Ruina Zhou ◽  
Jianhua Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Cell Carcinoma ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Gene Signature ◽  
Renal Clear Cell Carcinoma ◽  
Low Risk ◽  
Antioxidant Gene ◽  
Immune Infiltration

Background: Oxidative stress is related to oncogenic transformation in kidney renal clear cell carcinoma (KIRC). We intended to identify a prognostic antioxidant gene signature and investigate its relationship with immune infiltration in KIRC.Methods: With the support of The Cancer Genome Atlas (TCGA) database, we researched the gene expression and clinical data of KIRC patients. Antioxidant related genes with significant differences in expression between KIRC and normal samples were then identified. Through univariate and multivariate Cox analysis, a prognostic gene model was established and all patients were divided into high- and low-risk subgroups. Single sample gene set enrichment analysis was adopted to analyze the immune infiltration, HLA expression, and immune checkpoint genes in different risk groups. Finally, the prognostic nomogram model was established and evaluated.Results: We identified six antioxidant genes significantly correlated with the outcome of KIRC patients as independent predictors, namely DPEP1 (HR = 0.97, P &lt; 0.05), GSTM3 (HR = 0.97, P &lt; 0.05), IYD (HR = 0.33, P &lt; 0.05), KDM3B (HR = 0.96, P &lt; 0.05), PRDX2 (HR = 0.99, P &lt; 0.05), and PRXL2A (HR = 0.96, P &lt; 0.05). The high- and low-risk subgroups of KIRC patients were grouped according to the six-gene signature. Patients with higher risk scores had poorer prognosis, more advanced grade and stage, and more abundance of M0 macrophages, regulatory T cells, and follicular helper T cells. There were statistically significant differences in HLA and checkpoint gene expression between the two risk subgroups. The performance of the nomogram was favorable (concordance index = 0.766) and reliably predicted the 3-year (AUC = 0.792) and 5-year (AUC = 0.766) survival of patients with KIRC.Conclusion: The novel six antioxidant related gene signature could effectively forecast the prognosis of patients with KIRC, supply insights into the interaction between cellular antioxidant mechanisms and cancer, and is an innovative tool for selecting potential patients and targets for immunotherapy.

scholarly journals Analysis of gene expression signatures identifies prognostic and functionally distinct ovarian clear cell carcinoma subtypes

EBioMedicine ◽  
2019 ◽  
Vol 50 ◽  
pp. 203-210 ◽  
Author(s):  
Tuan Zea Tan ◽  
Jieru Ye ◽  
Chung Vin Yee ◽  
Diana Lim ◽  
Natalie Yan Li Ngoi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Carcinoma ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Ovarian Clear Cell Carcinoma ◽  
Gene Expression Signatures
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