Liquid biopsy proteomics of uveal melanoma reveals biomarkers associated with metastatic risk

Vélez, Gabriel; Nguyen, Huy; Chemudupati, Teja; Ludwig, Cassie A.; Toral, Marcus A.; Reddy, Sunil; Mruthyunjaya, Prithvi; Mahajan, Vinit B.

doi:10.1186/s12943-021-01336-4

Cited by 23 publications

(33 citation statements)

References 10 publications

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“…While we used mass spectrometric technology to quantify proteins, the pUM protein expression could be measured rapidly with high sensitivity and specificity with a multiplex immunoassay. Our prediction modeling results provide a foundation for antibody selection for developing such an immunoassay, a technology with emerging potential in the analysis of UM serum and vitreous specimens [ 58 , 59 ]. About 56% of the predictors in our model are probable cell surface proteins, a property that can facilitate the development of a liquid assay for blood-borne pUMs.…”

Section: Discussionmentioning

confidence: 99%

Proteomics of Primary Uveal Melanoma: Insights into Metastasis and Protein Biomarkers

Jang

Crabb

et al. 2021

Cancers

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Uveal melanoma metastases are lethal and remain incurable. A quantitative proteomic analysis of 53 metastasizing and 47 non-metastasizing primary uveal melanoma (pUM) was pursued for insights into UM metastasis and protein biomarkers. The metastatic status of the pUM specimens was defined based on clinical data, survival histories, prognostic analyses, and liver histopathology. LC MS/MS iTRAQ technology, the Mascot search engine, and the UniProt human database were used to identify and quantify pUM proteins relative to the normal choroid excised from UM donor eyes. The determined proteomes of all 100 tumors were very similar, encompassing a total of 3935 pUM proteins. Proteins differentially expressed (DE) between metastasizing and non-metastasizing pUM (n = 402) were employed in bioinformatic analyses that predicted significant differences in the immune system between metastasizing and non-metastasizing pUM. The immune proteins (n = 778) identified in this study support the immune-suppressive nature and low abundance of immune checkpoint regulators in pUM, and suggest CDH1, HLA-DPA1, and several DE immune kinases and phosphatases as possible candidates for immune therapy checkpoint blockade. Prediction modeling identified 32 proteins capable of predicting metastasizing versus non-metastasizing pUM with 93% discriminatory accuracy, supporting the potential for protein-based prognostic methods for detecting UM metastasis.

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Section: Discussionmentioning

confidence: 99%

Proteomics of Primary Uveal Melanoma: Insights into Metastasis and Protein Biomarkers

Jang

Crabb

et al. 2021

Cancers

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“…Recently, liquid biopsy proteomics data were published, revealing the biomarkers associated with metastatic risk. SCFR/c-Kit was among the top three proteins found to be upregulated in vitreous biopsies of UM patients compared to controls [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

KIT Expression Is Regulated by DNA Methylation in Uveal Melanoma Tumors

Kajabova

Šoltýsová

Demkova

et al. 2021

IJMS

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Uveal melanoma (UM) is an ocular tumor with a dismal prognosis. Despite the availability of precise molecular and cytogenetic techniques, clinicopathologic features with limited accuracy are widely used to predict metastatic potential. In 51 UM tissues, we assessed a correlation between the expression of nine proteins evaluated by immunohistochemistry (IHC) (Melan-A, S100, HMB45, Cyclin D1, Ki-67, p53, KIT, BCL2, and AIFM1) and the presence of UM-specific chromosomal rearrangements measured by multiplex ligation-dependent probe amplification (MLPA), to find IHC markers with increased prognostic information. Furthermore, mRNA expression and DNA methylation values were extracted from the whole-genome data, achieved by analyzing 22 fresh frozen UM tissues. KIT positivity was associated with monosomy 3, increasing the risk of poor prognosis more than 17-fold (95% CI 1.53–198.69, p = 0.021). A strong negative correlation was identified between mRNA expression and DNA methylation values for 12 of 20 analyzed positions, five located in regulatory regions of the KIT gene (r = −0.658, p = 0.001; r = −0.662, p = 0.001; r = −0.816; p < 0.001; r = −0.689, p = 0.001; r = −0.809, p < 0.001, respectively). DNA methylation β values were also inversely associated with KIT protein expression (p = 0.001; p = 0.001; p = 0.015; p = 0.025; p = 0.002). Our findings, showing epigenetic deregulation of KIT expression, may contribute to understanding the past failure to therapeutically target KIT in UM.

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“…As already mentioned, one of the most important field of application of liquid biopsy is oncology. A growing amount of studies are showing the relevance of this approach also in ocular oncology, not only to directly study the tumoral lesions but also to analyze the tumor-related microenvironment changes, detectable in ocular fluids [36][37][38].…”

Section: Safetymentioning

confidence: 99%

Intraocular fluid biomarkers (liquid biopsy) in human diabetic retinopathy

Midena

Frizziero

Midena

et al. 2021

Graefes Arch Clin Exp Ophthalmol

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Purpose This article aims to review the impact of detecting and quantifying intraocular biomarkers (liquid biopsy) in both aqueous and vitreous humor in eyes of people affected by diabetes mellitus. Methods This is a detailed review about aqueous and/or vitreous humor sampling in human diabetic eyes for proteomic and/or metabolomic analysis contributing to the understanding of the pathophysiology and treatment effects of diabetic retinopathy. Results Aqueous and vitreous humor molecular biomarkers proved to be directly correlated to each other and valuable to study retinal conditions. Moreover, proteomic and metabolomic analysis showed that the biomarkers of neuroinflammation, neurodegeneration, and vasculopathy are detectable in intraocular fluids and that their concentration changes in different stages of disease, and in response to treatment of all diabetic retinopathy aspects, mainly diabetic macular edema and proliferative retinopathy. Conclusions Liquid biopsy offers the possibility to improve our knowledge of intraocular eye disease induced by diabetes mellitus. The exact quantification of intraocular biomarkers contributes to the precision medicine approach even in the diabetic retinopathy scenario. The diffusion of this approach should be encouraged to have quantifiable information directly from the human model, which may be coupled with imaging data.

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Liquid biopsy proteomics of uveal melanoma reveals biomarkers associated with metastatic risk

Cited by 23 publications

References 10 publications

Proteomics of Primary Uveal Melanoma: Insights into Metastasis and Protein Biomarkers

Proteomics of Primary Uveal Melanoma: Insights into Metastasis and Protein Biomarkers

KIT Expression Is Regulated by DNA Methylation in Uveal Melanoma Tumors

Intraocular fluid biomarkers (liquid biopsy) in human diabetic retinopathy

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