Faculty Opinions recommendation of Lack of BAP1 protein expression in uveal melanoma is associated with increased metastatic risk and has utility in routine prognostic testing.

Malignant tumors are rarely homogenous on the morphological, genome, transcriptome or proteome level. In this study, we investigate the intratumor heterogeneity of BAP-1 expression in uveal melanoma with digital image analysis of 40 tumors. The proportion of BAP-1 positive cells was measured in full tumor sections, hot spots, cold spots and in scleral margins. The mean difference between hot spots and cold spots was 41 percentage points (pp, SD 29). Tumors with gene expression class 1 (associated with low metastatic risk) and 2 (high metastatic risk) had similar intratumor heterogeneity. Similarly, the level of intratumor heterogeneity was comparable in tumors from patients that later developed metastases as in patients that did not. BAP-1 measured in any tumor region added significant prognostic information to both American Joint Committee on Cancer (AJCC) tumor size category (p ≤ 0.001) and gene expression class (p ≤ 0.04). We conclude that there is substantial intratumor heterogeneity in uveal melanoma BAP-1 expression. However, it is of limited prognostic importance. Regardless of region, analysis of BAP-1 expression adds significant prognostic information beyond tumor size and gene expression class.

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Faculty Opinions recommendation of Liquid biopsy proteomics of uveal melanoma reveals biomarkers associated with metastatic risk.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.739655955.793584565 ◽

2021 ◽

Author(s):

Alison Skalet

Keyword(s):

Uveal Melanoma ◽

Liquid Biopsy ◽

Metastatic Risk

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Prospective evaluation of risk-appropriate management of uveal melanoma patients informed by gene expression profiling

Melanoma Management ◽

10.2217/mmt-2020-0001 ◽

2020 ◽

Vol 7 (1) ◽

pp. 17-25 ◽

Cited By ~ 1

Author(s):

Amy C Schefler ◽

Alison Skalet ◽

Scott C N Oliver ◽

John Mason ◽

Anthony B Daniels ◽

...

Keyword(s):

Gene Expression ◽

Uveal Melanoma ◽

Clinical Utility ◽

Medical Oncology ◽

Treatment Plan ◽

Risk Class ◽

Class 1 ◽

Melanoma Patients ◽

Metastatic Risk

Aim: The Clinical Application of DecisionDx-UM Gene Expression Assay Results study aimed to evaluate the clinical utility of the prognostic 15-gene expression profile (15-GEP) test for uveal melanoma (UM) patients in a large, prospective multicenter cohort. Patients & methods: Nine centers prospectively enrolled 138 UM patients clinically tested with the 15-GEP. Physician-recommended specialty referrals and metastatic surveillance regimens were collected. Results: A total of 93% of high-risk class 2 patients were referred to medical oncology for follow-up, compared with 51% of class 1 patients. A majority (62%) of class 2 patients were recommended overall high-intensity metastatic surveillance, while 85% of class 1 patients were recommended low-intensity metastatic surveillance. Conclusion: Treatment plan recommendations for UM patients are aligned with GEP-informed metastatic risk, consistent with prior studies.

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Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

Cancers ◽

10.3390/cancers12102832 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2832 ◽

Cited By ~ 2

Author(s):

Yamini Krishna ◽

Amelia Acha-Sagredo ◽

Dorota Sabat-Pośpiech ◽

Natalie Kipling ◽

Kim Clarke ◽

...

Keyword(s):

Protein Expression ◽

Uveal Melanoma ◽

Transcriptome Profiling ◽

Epithelioid Cell ◽

Formalin Fixed Paraffin ◽

Formalin Fixed Paraffin Embedded ◽

Galectin 3 ◽

Novel Biomarkers ◽

And Control ◽

Infiltrating Lymphocytes

Metastatic uveal melanoma (mUM) to the liver is incurable. Transcriptome profiling of 40 formalin-fixed paraffin-embedded mUM liver resections and 6 control liver specimens was undertaken. mUMs were assessed for morphology, nuclear BAP1 (nBAP1) expression, and their tumour microenvironments (TME) using an “immunoscore” (absent/altered/high) for tumour-infiltrating lymphocytes (TILs) and macrophages (TAMs). Transcriptomes were compared between mUM and control liver; intersegmental and intratumoural analyses were also undertaken. Most mUM were epithelioid cell-type (75%), amelanotic (55%), and nBAP1-ve (70%). They had intermediate (68%) or absent (15%) immunoscores for TILs and intermediate (53%) or high (45%) immunoscores for TAMs. M2-TAMs were dominant in the mUM-TME, with upregulated expression of ANXA1, CD74, CXCR4, MIF, STAT3, PLA2G6, and TGFB1. Compared to control liver, mUM showed significant (p < 0.01) upregulation of 10 genes: DUSP4, PRAME, CD44, IRF4/MUM1, BCL2, CD146/MCAM/MUC18, IGF1R, PNMA1, MFGE8/lactadherin, and LGALS3/Galectin-3. Protein expression of DUSP4, CD44, IRF4, BCL-2, CD146, and IGF1R was validated in all mUMs, whereas protein expression of PRAME was validated in 10% cases; LGALS3 stained TAMs, and MFGEF8 highlighted bile ducts only. Intersegmental mUMs show differing transcriptomes, whereas those within a single mUM were similar. Our results show that M2-TAMs dominate mUM-TME with upregulation of genes contributing to immunosuppression. mUM significantly overexpress genes with targetable signalling pathways, and yet these may differ between intersegmental lesions.

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High PTP4A3 Phosphatase Expression Correlates with Metastatic Risk in Uveal Melanoma Patients

Cancer Research ◽

10.1158/0008-5472.can-10-0605 ◽

2010 ◽

Vol 71 (3) ◽

pp. 666-674 ◽

Cited By ~ 67

Author(s):

Cécile Laurent ◽

Fabien Valet ◽

Nathalie Planque ◽

Licia Silveri ◽

Selma Maacha ◽

...

Keyword(s):

Uveal Melanoma ◽

Melanoma Patients ◽

Metastatic Risk

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Uveal Melanoma Biopsy: A Review

Cancers ◽

10.3390/cancers11081075 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1075 ◽

Cited By ~ 4

Author(s):

Luisa Frizziero ◽

Edoardo Midena ◽

Sara Trainiti ◽

Davide Londei ◽

Laura Bonaldi ◽

...

Keyword(s):

Uveal Melanoma ◽

Tissue Sample ◽

Current Model ◽

Local Treatment ◽

Clinical Findings ◽

Tumor Diagnosis ◽

Tumor Biopsy ◽

Additional Imaging ◽

Metastatic Risk ◽

Sampling Procedures

Intraocular tumor diagnosis is based on clinical findings supported by additional imaging tools, such as ultrasound, optical coherence tomography and angiographic techniques, usually without the need for invasive procedures or tissue sampling. Despite improvements in the local treatment of uveal melanoma (UM), the prevention and treatment of the metastatic disease remain unsolved, and nearly 50% of patients develop liver metastasis. The current model suggests that tumor cells have already spread by the time of diagnosis, remaining dormant until there are favorable conditions. Tumor sampling procedures at the time of primary tumor diagnosis/treatment are therefore now commonly performed, usually not to confirm the diagnosis of UM, but to obtain a tissue sample for prognostication, to assess patient’s specific metastatic risk. Moreover, several studies are ongoing to identify genes specific to UM tumorigenesis, leading to several potential targeted therapeutic strategies. Genetic information can also influence the surveillance timing and metastatic screening type of patients affected by UM. In spite of the widespread use of biopsies in general surgical practice, in ophthalmic oncology the indications and contraindications for tumor biopsy continue to be under debate. The purpose of this review paper is to critically evaluate the role of uveal melanoma biopsy in ophthalmic oncology.

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Die Tumorheterogenität des uvealen Melanoms: Diagnostisch und prognostisch wichtig?

Karger Kompass Ophthalmologie ◽

10.1159/000518309 ◽

2021 ◽

pp. 1-3

Author(s):

Ira Seibel

Keyword(s):

Uveal Melanoma ◽

Treatment Strategies ◽

Intratumoral Heterogeneity ◽

Correct Prediction ◽

Patient Counseling ◽

Clinical Behavior ◽

Precise Information ◽

Genetic Features ◽

Metastatic Risk ◽

Tumor Biopsies

Tumor biopsies in uveal melanoma (UM) serve mainly the purpose of prognostication and assessment of individual metastatic risk, but can be used for diagnosis in selected cases. The importance of precise information is paramount for selecting adequate surveillance protocols, patient counseling, and optimization of treatment strategies. However, intratumoral heterogeneity and sample representativity are major concerns and can interfere with the correct prediction of the patient’s prognosis. We report a series of cases of UM with distinct morphologically identifiable areas, highlighting the differences in clinical behavior, as well as histopathological and genetic features.

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