Multi-omics Profiling Shows BAP1 Loss Is Associated with Upregulated Cell Adhesion Molecules in Uveal Melanoma

Baqai, Usman; Purwin, Timothy J.; Bechtel, Nelisa; Chua, Vivian; Han, Anna; Hartsough, Edward J.; Kuznetsoff, Jeffim N.; Harbour, J. William; Aplin, Andrew E.

doi:10.1158/1541-7786.mcr-21-0657

Cited by 12 publications

(10 citation statements)

References 72 publications

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“…Another explanation is that SDC2 may have complex interactions with other genes and the function of SDC2 may be realized by participation of other genes. Interestingly, a recent study showed that BAP1 loss is associated with upregulated expression of SDC2 in UVM, while knockdown of SDC2 did not have any functional inhibition [47]. Considering that single knockdown of SDC2 has not overt effect, further studies are needed to determine the exact role of SDC2 in UVM.…”

Section: Discussionmentioning

confidence: 99%

A Novel Glycolysis-Related Signature for Predicting the Prognosis and Immune Infiltration of Uveal Melanoma

Guo

Zhang

et al. 2023

Ophthalmic Res

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Introduction As the most common aggressive intraocular cancer in adults, uveal melanoma (UVM) threatens the survival and vision of many people. Glycolysis is a novel hallmark of cancer, but the role of glycolysis-related genes in UVM prognosis remains unknown. The purpose of the study was to establish a glycolysis-related gene signature (GRGS) to predict UVM prognosis. Methods Raw data were obtained from TCGA-UVM and GSE22138 datasets. The GRGS was established by univariate, LASSO and multivariate Cox regression analyses. Kaplan‒Meier survival and time-dependent receiver operating characteristic curves were used to evaluate the predictive ability of the GRGS. The relationships of the GRGS with infiltrating immune cell levels and mutations were analyzed with CIBERSORT and maftools. Results A novel GRGS (risk score = 0.690861*ISG20 +0.070991*MET -0.227520*SDC2 +0.690223*FBP1 +0.048008*CLN6-0.128520* SDC3) was developed for predicting UVM prognosis. The GRGS had robust predictive stability in UVM. Enrichment annotation suggested that the high-risk group had stronger adaptive immune responses and that the low-risk group had more innate immune cell infiltration. Moreover, BAP1 mutation was related to high risk, and SF3B1 mutation was related to low risk. Conclusions This study developed and validated a novel GRGS to predict UVM prognosis and immune infiltration. The signature revealed an association between glycolysis-related genes and the tumor microenvironment, providing new insights into the role of glycolysis in UVM.

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Section: Discussionmentioning

confidence: 99%

A Novel Glycolysis-Related Signature for Predicting the Prognosis and Immune Infiltration of Uveal Melanoma

Guo

Zhang

et al. 2023

Ophthalmic Res

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“…Loss-of-function BAP1 mutations are associated with higher tumor grade and poorer prognosis in ccRCC [ 26 ]. Previous research in uveal melanoma demonstrated that BAP1 could regulate the expression of multiple cell adhesion molecules [ 27 ]. As one adhesion molecule, BCAM may also be regulated by BAP1 in ccRCC, although there is no evidence yet.…”

Section: Discussionmentioning

confidence: 99%

Integrated multi-omics analyses reveal that BCAM is associated with epigenetic modification and tumor microenvironment subtypes of clear cell renal cell carcinoma

et al. 2022

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Background Clear cell renal cell carcinoma (ccRCC) is the most common and highly heterogeneous subtype of renal cell carcinoma. Dysregulated basal cell adhesion molecule (BCAM) gene is associated with poor prognosis in various cancers. However, the dysregulated functions and related multi-omics features of BCAM in ccRCC stay unclear. Results BCAM expression was aberrantly downregulated in ccRCC and correlated with adverse pathological parameters and poor prognosis. Low mRNA expression of BCAM was remarkably associated with its CpG methylation levels and BAP1 mutation status. Patients with lower-expressed BCAM concomitant with BAP1 mutation had a worse prognosis. Using RNA-seq data from The cancer genome atlas, we found that compared to the BCAM-high expression subgroup, ccRCC patients in the BCAM-low expression subgroup had significantly higher levels of immune infiltration, higher immune checkpoint expression levels and lower TIDE (tumor immune dysfunction and exclusion) score, indicating potential better response to immunotherapy. Data from the Clinical Proteomic Tumor Analysis Consortium further validated the association between low BCAM expression and CD8 + inflamed phenotype at protein level. Meanwhile, our results suggested that the angiogenesis-related pathways were enriched in the BCAM-high expression subgroup. More importantly, according to the data from the GDSC database, we revealed that the BCAM-high expression subgroup should be more sensitive to anti-angiogenetic therapies, including sorafenib, pazopanib and axitinib. Conclusions These results suggest that BCAM could serve as a biomarker distinguishing different tumor microenvironment phenotypes, predicting prognosis and helping therapeutic decision-making for patients with ccRCC.

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“…A recent paper [49] proposed that the cell adhesion molecules CADM1, SDC2 and CDH1 are up-regulated in BAP1 mutant human UM. While these three genes were also up-regulated in our analysis of human UM, Cadm1 and Sdc2 were not DE in the mouse dataset and Cdh1 (Ecadherin) was down-regulated, which is more consistent with an up-regulation of EMT, the general overall pattern that we observed.…”

Section: Shared Transcriptional Changes In Bap1 Mutant Um Identify Em...mentioning

confidence: 99%

BAP1 deficient human and mouse uveal melanomas up-regulate a shared EMT pathway

Farag

Jain

Luty

et al. 2023

Preprint

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Monosomy 3 is a negative indicator for uveal melanoma (UM). A key tumor suppressor on chromosome 3 is the deubiquitinase BAP1, which usually has a second hit in cases with monosomy 3. Here, we investigated the role of Bap1 loss in the GNAQ Q209L mouse UM model. We found that heterozygous Bap1 mutations increased the proportion of lung lesions reaching an unusually large size and permitted the growth of liver lesions. Comparison of RNAseq data from mouse and human UM identified a set of 270 genes differentially expressed in the same direction when BAP1 is mutant. The most significant pathway in this gene set was Epithelial to Mesenchymal Transition (EMT). The expression of five apical junction complex genes known to be down-regulated in association with EMT was very significantly correlated with survival in human UM patients. Activation of EMT through Bap1 deficiency could increase melanoma plasticity and adaptation to new microenvironments.

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Multi-omics Profiling Shows BAP1 Loss Is Associated with Upregulated Cell Adhesion Molecules in Uveal Melanoma

Cited by 12 publications

References 72 publications

A Novel Glycolysis-Related Signature for Predicting the Prognosis and Immune Infiltration of Uveal Melanoma

A Novel Glycolysis-Related Signature for Predicting the Prognosis and Immune Infiltration of Uveal Melanoma

Integrated multi-omics analyses reveal that BCAM is associated with epigenetic modification and tumor microenvironment subtypes of clear cell renal cell carcinoma

BAP1 deficient human and mouse uveal melanomas up-regulate a shared EMT pathway

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