Dataset Information

DNA Repair Genes Are Associated with Subtype Classification, Prognosis, and Immune Infiltration in Uveal Melanoma.

ABSTRACT: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. DNA repair genes play a vital role in cancer development. However, there has been very little research about DNA repair genes in UM. This study aimed to evaluate the importance of DNA repair genes and established a signature for predicting prognosis and immune features of UM. In this study, we mined TCGA database through bioinformatics analysis, and the intersect was taken between DNA repair genes and prognosis related genes and yielded 52 genes. We divided 80 UM patients into C1 and C2 subtypes. GSEA results indicated that abundant cancer-promoting functions and signaling pathways were activated in C2 subtype and the proportion of SNVs was higher in C2 than in C1 which suggested a worse prognosis. We built a six DNA repair genes model including ITPA, CETN2, CCNO, POLR2J, POLD1, and POLA1 by LASSO regression to predict prognosis of UM patients and utilized the median value of risk scores as the cutoff point to differentiate high risk and low risk group. The survival analyses and the receiver operating characteristic (ROC) curves in the validation group and entire data set confirmed the accuracy of this model. We also constructed a nomogram based on age and risk scores to evaluate the relationship between risk scores and clinical outcome. The calibration curve of the overall survival (OS) indicated that the performance of this model is steady and robust. Finally, the enrichment analysis showed that there were complex regulatory mechanisms in UM patients. The immune infiltration analysis indicated that the immune infiltration in C2 in the high risk group was different from that in the low risk group. Our findings indicated that the DNA repair genes may be related to UM prognosis and provide new insight into the underlying mechanisms.

SUBMITTER: Wang T

PROVIDER: S-EPMC8791741 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundDNA damage repair plays an important role in the onset and progression of cancers and its resistance to treatment therapy. This study aims to assess the prognostic potential of DNA damage repair markers in skin cutaneous melanoma (SKCM).MethodIn this study, we have analyzed the gene expression profiles being downloaded from TCGA, GTEx, and GEO databases. We sequentially used univariate and LASSO Cox regression analyses to screen DNA repair genes associated with prognosis. Then, we have conducted a multivariate regression analysis to construct the prognostic profile of DNA repair-related genes (DRRGs). The risk coefficient is used to calculate the risk scores and divide the patients into two cohorts. Additionally, we validated our prognosis model on an external cohort as well as evaluated the link between immune response and the DRRGs prognostic profiles. The risk signature is compared to immune cell infiltration, chemotherapy, and immune checkpoint inhibitors (ICIs) treatment.ResultsAn analysis using LASSO-Cox stepwise regression established a prognostic signature consisting of twelve DRRGs with strong predictive ability. Disease-specific survival (DSS) is found to be lower among high-risk patients group as compared to low-risk patients. The signature may be employed as an independent prognostic predictor after controlling for clinicopathological factors, as demonstrated by validation on one external GSE65904 cohort. A strong correlation is also found between the risk score and the immune microenvironment, along with the infiltrating immune cells, and ICIs key molecules. The gene enrichment analysis results indicate a wide range of biological activities and pathways to be exhibited by high-risk groups. Furthermore, Cisplatin exhibited a considerable response sensitivity in low-risk groups as opposed to the high-risk incidents, while docetaxel exhibited a considerable response sensitivity in high-risk groups.ConclusionsOur findings provide a thorough investigation of DRRGs to develop an DSS-related prognostic indicator which may be useful in forecasting SKCM progression and enabling more enhanced clinical benefits from immunotherapy.

Project description:BackgroundIn uveal melanomas, immune infiltration is a marker of poor prognosis. This work intended to decipher the biological characteristics of intra-tumor immune population, compare it to other established biomarkers and to patients' outcome.MethodsPrimary, untreated, and mainly large uveal melanomas with retinal detachment were analyzed using: transcriptomic profiling (n = 15), RT-qPCR (n = 36), immunohistochemistry (n = 89), Multiplex Ligation-dependent Probe Amplification (MLPA) for copy number alterations (CNA) analysis (n = 89), array-CGH (n = 17), and survival statistics (n = 86).ResultsGene expression analysis divided uveal melanomas into two groups, according to the IFNγ/STAT1-IRF1 pathway activation. Tumors with IFNγ-signature had poorer prognosis and showed increased infiltration of CD8+ T lymphocytes and macrophages. Cox multivariate analyses of immune cell infiltration with MLPA data delineated better prognostic value for three prognostic groups (three-tier stratification) than two (two-tier stratification). CNA-based model comprising monosomy 3, 8q amplification, and LZTS1and NBL1 deletions emerged as the best predictor for disease-free survival. It outperformed immune cell infiltration in receiver operating characteristic curves. The model that combined CNA and immune infiltration defined risk-groups according to the number of DNA alterations. Immune cell infiltration was increased in the high-risk group (73.7%), where it did not correlate with patient survival, while it was associated with poorer outcome in the intermediate risk-group.ConclusionsHigh degree of immune cell infiltration occurs in a subset of uveal melanomas, is interferon-gamma-related, and associated with poor survival. It allows for two-tier stratification, which is prognostically less efficient than a three-tier one. The best prognostic stratification is by CNA model with three risk-groups where immune cell infiltration impacts only some subgroups.

Project description:Skin cutaneous melanoma (SKCM, hereafter referred to as melanoma) is the most lethal skin cancer with increasing incidence. Regulated cell death plays an important role in tumorigenesis and serves as an important target for almost all treatment strategies. Cuproptosis is the most recently identified copper-dependent regulated cell death form that relies on mitochondria respiration. However, its role in tumorigenesis remains unknown. The correlation of cuproptosis-related genes with tumor prognosis is far to be understood, either. In the present study, we explored the correlation between cuproptosis-related genes with the prognosis of melanoma by accessing and analyzing a public database and found 11 out 12 genes were upregulated in melanoma tissues and three genes (LIPT1, PDHA1, and SLC31A1) have predictive value for the prognosis. The subgroup of melanoma patients with higher cuproptosis-related gene expression showed longer overall survival than those with lower gene expression. We chose LIPT1 for further exploration. LIPT1 expression was increased in melanoma biopsies and was an independent favorable prognostic indicator for melanoma patients. Moreover, LIPT1 expression was positively correlated with PD-L1 expression and negatively associated with Treg cell infiltration. The melanoma patients with higher LIPT1 expression showed longer overall survival than those with lower LIPT1 expression after receiving immunotherapy, indicating the prognostic predictive value of LIPT1. Finally, a pan-cancer analysis indicated that LIPT1 was differentially expressed in diverse cancers as compared to normal tissues and correlated with the expression of multiple immune checkpoints, especially PD-L1. It could serve as a favorable prognosis indicator in some cancer types. In conclusion, our study demonstrated the prognostic value of cuproptosis-related genes, especially LIPT1, in melanoma, and revealed the correlation between LIPT1 expression and immune infiltration in melanoma, thus providing new clues on the prognostic assessment of melanoma patients and providing a new target for the immunotherapy of melanoma.

Project description:BackgroundTAP1 is an immunomodulation-related protein that plays different roles in various malignancies. This study investigated the transcriptional expression profile of TAP1 in uveal melanoma (UVM), revealed its potential biological interaction network, and determined its prognostic value.MethodsCIBERSORT and ESTIMATE bioinformatic methods were used on data sourced from The Cancer Genome Atlas database (TCGA) to determine the correlation between TAP1 expression, UVM prognosis, biological characteristics, and immune infiltration. Gene set enrichment analysis (GSEA) was used to discover the signaling pathways associated with TAP1, while STRING database and CytoHubba were used to construct protein-protein interaction (PPI) and competing endogenous RNA (ceRNA) networks, respectively. An overall survival (OS) prognostic model was constructed to test the predictive efficacy of TAP1, and its effect on the in vitro proliferation activity and metastatic potential of UVM cell line C918 cells was verified by RNA interference.ResultsThere was a clear association between TAP1 expression and UVM patient prognosis. Upregulated TAP1 was strongly associated with a shorter survival time, higher likelihood of metastasis, and higher mortality outcomes. According to GSEA analysis, various immunity-related signaling pathways such as primary immunodeficiency were enriched in the presence of elevated TAP1 expression. A PPI network and a ceRNA network were constructed to show the interactions among mRNAs, miRNAs, and lncRNAs. Furthermore, TAP1 expression showed a significant positive correlation with immunoscore, stromal score, CD8+ T cells, and dendritic cells, whereas the correlation with B cells and neutrophils was negative. The Cox regression model and calibration plots confirmed a strong agreement between the estimated OS and actual observed patient values. In vitro silencing of TAP1 expression in C918 cells significantly inhibited cell proliferation and metastasis.ConclusionsThis study is the first to demonstrate that TAP1 expression is positively correlated with clinicopathological factors and poor prognosis in UVM. In vitro experiments also verified that TAP1 is associated with C918 cell proliferation, apoptosis, and metastasis. These results suggest that TAP1 may function as an oncogene, prognostic marker, and importantly, as a novel therapeutic target in patients with UVM.

Dataset Information

DNA Repair Genes Are Associated with Subtype Classification, Prognosis, and Immune Infiltration in Uveal Melanoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets