Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma

Patrone, Serena; Maric, Irena; Rutigliani, Mariangela; Lanza, Francesco; Puntoni, Matteo; Banelli, Barbara; Rancati, Silvia; Ángelini, Giovanna; Amaro, Adriana; Ligorio, Paolo; Defferrari, Carlotta; Castagnetta, Mauro; Bandelloni, Roberto; Mosci, Carlo; DeCensi, Andrea; Romani, Massimo; Pfeffer, Urlich; Viaggi, Silvia; Coviello, Domenico

doi:10.1002/gcc.22541

Cited by 23 publications

(16 citation statements)

References 62 publications

(154 reference statements)

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“…These gene mutations were not identified in the cutaneous melanoma, which was consistent with the literature 31. Mutations in GNAQ (50%) and GNA11 (44%) are early events that promote cell proliferation, suggesting that activated G-protein signaling plays a crucial role in early uveal melanoma development 12. In addition to mutated genes mentioned above, uveal melanoma also harbored additional SF3B1 (22%), EIF1AX (12%), COL14A1 (4%), CYSLTR2 (4%), MACF1 (4%), MUC16 (4%) and MYOF (4%).…”

Section: Discussionsupporting

confidence: 87%

“…BAP1 mutations are related to metastasis and EIF1AX mutations are associated with favorable metastatic-free survival 7-10. Uveal melanoma patients with chromosome 3 copy number loss are associated with a high risk of metastasis and a poor outcome 11, 12. It was reported that UM tumor progression typically displays chromosomal abnormalities.…”

Section: Introductionmentioning

confidence: 99%

“…It was reported that UM tumor progression typically displays chromosomal abnormalities. UM patients with chromosome 3 loss, 8q gain and 1p loss have reduced overall survival 12. Therefore, exploring the gene mutations and copy number variations may provide insights into uveal melanoma prognosis.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Prognostic Signatures for Predicting the Overall Survival of Uveal Melanoma Patients

et al. 2019

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Uveal melanoma (UM) is an aggressive cancer which has a high percentage of metastasis and with a poor prognosis. Identifying the potential prognostic markers of uveal melanoma may provide information for early detection of metastasis and treatment. In this work, we analyzed 80 uveal melanoma samples from The Cancer Genome Atlas (TCGA). We developed an 18-gene signature which can significantly predict the prognosis of UM patients. Firstly, we performed a univariate Cox regression analysis to identify significantly prognostic genes in uveal melanoma (P<0.01). Then the glmnet Cox analysis was used to generate a powerful prognostic gene model. Further, we established a risk score formula for every patient based on the 18-gene prognostic model with multivariate Cox regression. We stratified patients into high- and low-risk subtypes with median risk score and found that patients in high-risk group had worse prognosis than patients in low-risk group. Multivariate Cox regression analysis demonstrated that 18-gene model risk score was independent of clinical prognostic factors. We identified four genes whose mutations were closely to UM patients' prognosis or risk score. We also explored the relationship between copy number variation and risk score and found that high risk group showed more chromosome aberrations than low risk group. Gene Set Enrichment Analysis (GSEA) analysis showed that the different biological pathways and functions between low and high risk group. In summary, our findings constructed an 18-gene signature for estimating overall survival (OS) of UM. Patients were categorized into two subtypes based on the risk score and we found that high risk group showed more chromosome aberrations than low risk group.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Identification of Prognostic Signatures for Predicting the Overall Survival of Uveal Melanoma Patients

et al. 2019

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“…The monosomy 3 tumors from both groups C and D showed gain of the entire 8q arm in nearly all samples as reported previously in TCGA cohort (20). Patients with monosomy 3, 8p loss, and 8q gain had lower overall survival (OS) as described elsewhere (30)(31)(32)(33)(34)(35). When examined independently, chromosomal alterations associated with metastatic disease were loss of 3p (P ¼ 2.29 Â 10 À8 ), loss of 3q (P ¼ 2.95 Â 10 À7 ), loss of 6q (P ¼ 0.0246), gain of 8q (P ¼ 0.0001), and loss of…”

Section: Broad Copy Number Alterations In Uveal Melanomasupporting

confidence: 78%

Integrative Copy Number Analysis of Uveal Melanoma Reveals Novel Candidate Genes Involved in Tumorigenesis Including a Tumor Suppressor Role for PHF10/BAF45a

Anbunathan

Verstraten

Singh

et al. 2019

Clinical Cancer Research

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Purpose: Uveal melanoma is a primary malignancy of the eye with oncogenic mutations in GNAQ, GNA11, or CYSLTR2, and additional mutations in BAP1 (usually associated with LOH of Chr 3), SF3B1, or EIF1AX. There are other characteristic chromosomal alterations, but their significance is not clear. Experimental Design: To investigate genes driving chromosomal alterations, we integrated copy number, transcriptome, and mutation data from three cohorts and followed up key findings. Results: We observed significant enrichment of transcripts on chromosomes 1p, 3, 6, 8, and 16q and identified seven shared focal copy number alterations (FCNAs) on Chr 1p36, 2q37, 3, 6q25, 6q27, and 8q24. Integrated analyses revealed clusters of genes in focal copy number regions whose expression was associated with metastasis and worse overall survival. This included genes from Chr 1p36, 3p21, and 8q24.3. At Chr 6q27, we identified two tumors with homozygous deletion of PHF10/BAF45a and one with a frameshift mutation with concomitant loss of the wild-type allele. Downregulation of PHF10 in uveal melanoma cell lines and tumors altered a number of biological pathways including development and adhesion. These findings provide support for a role for PHF10 as a novel tumor suppressor at Chr 6q27. Conclusions: Integration of copy number, transcriptome, and mutation data revealed novel candidate genes playing a role in uveal melanoma pathogenesis and a potential tumor suppressor role for PHF10.

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“…Dysregulation of BAP1 exclusively occurs in UM progression and exhibits a strong correlation to UM metastasis. Recently, Patrone et al 6 revealed that loss of BAP1 protein was significantly associated with prolonged progression-free survival in patients with UM. Moore et al 7 demonstrated that RasGRP3 is a potential target and it is specifically required for Ras activation and tumorigenesis of UM cells.…”

Section: Introductionmentioning

confidence: 99%

An 11‐gene‐based prognostic signature for uveal melanoma metastasis based on gene expression and DNA methylation profile

Yang

et al. 2018

J of Cellular Biochemistry

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Uveal melanoma (UM) is the most common intraocular tumor worldwide. We proposed to identify a vital gene signature that has prognostic value for UM metastasis. For this purpose, we obtained a published DNA methylation and gene expression data set associated with UM from the Gene Expression Omnibus. The genes whose aberrant expression significantly associated with UM patients’ metastasis‐free survival (MFS) were identified by applying a univariate Cox proportional hazards model to the gene expression data set followed by a robust likelihood‐based survival analysis to screen the optimal prognostic gene signatures (PGS). A formula for calculating the risk score that represents UM metastasis risk was constructed by including the PGSs’ expression values weighted by their regression coefficients, which were obtained by a multivariate Cox regression analysis. As a result, aberrant expression of 2884 genes were found to be significantly associated with UM patients’ MFS, which were referred to as MFSGs, and 11 out of those MFSGs, GJC1, TCEA1, MFSD3, FAF2, TLCD1, GPAA1, CYC1, ASAP1, JPH1, LDB3, and KDELR3, were identified as PGSs through which we could accurately separate UM samples with shorter MFS from those with longer MFS. By combining the DNA methylation data set and MFSGs, we further identified 265 MFSGs, which contained CpG sites that significantly hyper‐ or hypo‐methylated in UM samples compared with control samples. Functional enrichment analysis and pathway crosstalk analysis of those genes indicated significant enrichment of cancer‐related pathways. In conclusion, we identified an 11‐gene‐based prognostic signature and several gene biomarkers for UM metastasis, which should be helpful for selecting an appropriate treatment method for specific patients with UM.

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Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma

Cited by 23 publications

References 62 publications

Identification of Prognostic Signatures for Predicting the Overall Survival of Uveal Melanoma Patients

Identification of Prognostic Signatures for Predicting the Overall Survival of Uveal Melanoma Patients

Integrative Copy Number Analysis of Uveal Melanoma Reveals Novel Candidate Genes Involved in Tumorigenesis Including a Tumor Suppressor Role for PHF10/BAF45a

An 11‐gene‐based prognostic signature for uveal melanoma metastasis based on gene expression and DNA methylation profile

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