DNA alteration‐based classification of uveal melanoma gives better prognostic stratification than immune infiltration, which has a neutral effect in high‐risk group

Narasimhaiah, Deepti; Legrand, Catherine; Damotte, Diane; Remark, Romain; Munda, Marco; Potter, Patrick De; Coulie, Pierre G.; Vikkula, Miikka; Godfraind, Catherine

doi:10.1002/cam4.2122

Cited by 12 publications

(10 citation statements)

References 35 publications

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“…While our results need further verification in different experimental settings, the CIBERSORTx algorithm we employed has been extensively validated with techniques such as flow cytometry, mass cytometry, immunohistochemistry, and single-cell RNA-seq by multiple different groups, providing robust data confirming its accuracy [40,[63][64][65]. Nevertheless, others have already created mRNA/miRNA/DNA-based scores with strong prognostic values in UM tumors [33,[66][67][68][69][70][71][72]. Rather than compete with them, our foremost motive for creating the cell type-based prognostic score was to select the cell types playing a prime role in the biology of UM progression Previous research has identified extensive lymphocyte infiltration as a negative prognostic factor in UM; however, the prognostic role of individual subsets was not assessed Another dominant subset of tumor-infiltrating immune cells is macrophages.…”

Section: Journal Of Immunology Researchmentioning

confidence: 75%

Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression

Lachota

Lennikov

Malmberg

et al. 2021

Journal of Immunology Research

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Tumor-infiltrating immune cells are capable of effective cancer surveillance, and their abundance is linked to better prognosis in numerous tumor types. However, in uveal melanoma (UM), extensive immune infiltrate is associated with poor survival. This study aims to decipher the role of different tumor-infiltrating cell subsets in UM in order to identify potential targets for future immunotherapeutic treatment. We have chosen the TCGA-UVM cohort as a training dataset and GSE22138 as a testing dataset by mining publicly available databases. The abundance of 22 immune cell types was estimated using CIBERSORTx. Then, to determine the significance of tumor-infiltrating cell subsets in UM, we built a multicell type prognostic signature, which was validated in the testing cohort. The created signature was built upon the negative prognostic role of CD8+ T cells and M0 macrophages and the positive role of neutrophils. Based on the created signature score, we divided the patients into low- and high-risk groups. Kaplan-Meier, Cox, and ROC analyses demonstrated superior performance of our risk score compared to either clinical or pathologic characteristics of both cohorts. Further, we found the molecular pathways associated with cancer immunoevasion and metastasis to be enriched in the high-risk group, explaining both the lack of adequate immune surveillance despite increased infiltration of CD8+ T cells as well as the higher metastatic potential. Genes associated with tryptophan metabolism (IDO1 and KYNU) and metalloproteinases were among the most differentially expressed between the high- and low-risk groups. Our correlation analyses interpreted in context of published in vitro data strongly suggest the central role of CD8+ T cells in shifting the UM tumor microenvironment towards suppressive and metastasis-promoting. Therefore, we propose further investigations of IDO1 and metalloproteinases as novel targets for immunotherapy in lymphocyte-rich metastatic UM patients.

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Section: Journal Of Immunology Researchmentioning

confidence: 75%

Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression

Lachota

Lennikov

Malmberg

et al. 2021

Journal of Immunology Research

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“…One recent study has demonstrated that loss of BAP1 expression is strongly associated with immune modulation of the microenvironment, and it makes an impact on the immunotherapy of UM [35]. Furthermore, Narasimhaiah et al found that immune cell infiltration was associated with poorer outcomes in the intermediate-risk group and increased in the high-risk group, indicating that immune infiltration may be a promising biomarker repository for better-personalized management of UM [10]. Our research on genes involved in the microenvironment of UM provides an opportunity for the development of therapeutic agents or gene targets.…”

Section: Plos Onementioning

confidence: 99%

“…Narasimhaiah and colleagues found that UM with IFNγ-signature had a poorer prognosis and showed increased infiltration of CD8+ T lymphocytes and macrophages. In UM, it was demonstrated that immune cell infiltration was associated with poorer outcomes in the intermediate-risk group and increased in high-risk group (73.7%) [10]. ESTIMATE, designed by Yoshihara et al, is a tool for predicting tumor purity, and the presence of infiltrating stromal/immune cells in tumor tissues using gene expression data [11].…”

Section: Introductionmentioning

confidence: 99%

Identification of prognostic genes in uveal melanoma microenvironment

Luo

2020

PLoS ONE

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Background Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Many previous studies have demonstrated that the infiltrating of immune and stromal cells in the tumor microenvironment contributes significantly to prognosis. Methods Dataset TCGA-UVM, download from TCGA portal, was taken as the training cohort, and GSE22138, obtained from GEO database, was set as the validation cohort. ESTIMATE algorithm was applied to find intersection differentially expressed genes (DEGs) among tumor microenvironment. Kaplan-Meier analysis and univariate Cox regression model were performed on intersection DEGs to initial screen for potential prognostic genes. Then these genes entered into the validation cohort for validation using the same methods as that in the training cohort. Moreover, we conducted correlation analyses between the genes obtained in the validation cohort and the status of chromosome 3, chromosome 8q, and tumor metastasis to get prognosis genes. At last, the immune infiltration analysis was performed between the prognostic genes and 6 main kinds of tumor-infiltrating immune cells (TICs) for understanding the role of the genes in the tumor microenvironment. Results 959 intersection DEGs were found in the UM microenvironment. Kaplan-Meier and Cox analysis was then performed in the training and validation cohorts on these DEGs, and 52 genes were identified with potential prognostic value. After comparing the 52 genes to chromosome 3, chromosome 8q, and metastasis, we obtained 21 genes as the prognostic genes. The immune infiltration analysis showed that Neutrophil had the potential prognostic ability, and almost every prognostic gene we had identified was correlated with abundances of Neutrophil and CD8+ T Cell. Conclusions Identifying 21 prognosis genes (SERPINB9, EDNRB, RAPGEF3, HFE, RNF43, ZNF415, IL12RB2, MTUS1, NEDD9, ZNF667, AZGP1, WARS, GEM, RAB31, CALHM2, CA12, MYEOV, CELF2, SLCO5A1, ISM1, and PAPSS2) could accurately identify patients' prognosis and had close interactions with Neutrophil in the tumor environment, which may provide UM patients with personalized prognosis prediction and new treatment insights.

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“…Notably, SLCO5A1 was considered as a prognosis gene correlated with the immune infiltrates. The immune cell infiltration level was noted to be a crucial factor in predicting the UM prognosis ( 33 ). Supplementally, we sought out that BAP1 was associated with abnormal DNA methylation within IntSub2 samples rather than other subtypes.…”

Section: Resultsmentioning

confidence: 99%

Re-Identification of Patient Subgroups in Uveal Melanoma

Nguyen¹,

Nguyen²,

Nguyen³

et al. 2021

Front. Oncol.

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Uveal melanoma (UM) is a comparatively rare cancer but requires serious consideration since patients with developing metastatic UM survive only for about 6–12 months. Fortunately, increasingly large multi-omics databases allow us to further understand cancer initiation and development. Moreover, previous studies have observed that associations between copy number aberrations (CNA) or methylation (MET) versus messenger RNA (mRNA) expression have affected these processes. From that, we decide to explore the effect of these associations on a case study of UM. Also, the current subtypes of UM display its weak association with biological phenotypes and its lack of therapy suggestions. Therefore, the re-identification of molecular subtypes is a pressing need. In this study, we recruit three omics profiles, including CNA, MET, and mRNA, in a UM cohort from The Cancer Genome Atlas (TCGA). Firstly, we identify two sets of genes, CNAexp and METexp, whose CNA and MET significantly correlated with their corresponding mRNA, respectively. Then, single and integrative analyses of the three data types are performed using the PINSPlus tool. As a result, we discover two novel integrative subgroups, IntSub1 and IntSub2, which could be a useful alternative classification for UM patients in the future. To further explore molecular events behind each subgroup, we identify their subgroup-specific genes computationally. Accordingly, the highest expressed genes among IntSub1-specific genes are mostly enriched with immune-related processes. On the other hand, IntSub2-specific genes are highly associated with cellular cation homeostasis, which responds effectively to chemotherapy using ion channel inhibitor drugs. In addition, we detect that the two integrative subgroups show different age-related risks and survival rates. These discoveries can influence the frequency of metastatic surveillance and support medical practitioners to choose an appropriate treatment regime.

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DNA alteration‐based classification of uveal melanoma gives better prognostic stratification than immune infiltration, which has a neutral effect in high‐risk group

Cited by 12 publications

References 35 publications

Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression

Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression

Identification of prognostic genes in uveal melanoma microenvironment

Re-Identification of Patient Subgroups in Uveal Melanoma

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