Molecular Characteristics of Uveal Melanoma: Insights from the Cancer Genome Atlas (TCGA) Project

Bakhoum, Mathieu F.; Esmaeli, Bita

doi:10.3390/cancers11081061

Cited by 60 publications

(77 citation statements)

References 74 publications

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“…Although higher cytotoxic expression patterns are associated with better anti-tumor response and better patient survival in many solid tumors [34,41,42], the prognostic effects of immune infiltration depend on the type of tumor, the location of the cells and the state of activation. In UM, high levels of immune cells are associated with poor prognostic factors, such as M3 and BAP1 mutation [15,17,43]. Immune cell infiltration occurs more frequently in epithelioid-cell-type UM, which also has a poor prognosis [44].…”

Section: Discussionmentioning

confidence: 99%

Immunological analyses reveal an immune subtype of uveal melanoma with a poor prognosis

Pan

Liu

Cui

et al. 2020

Aging

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Uveal melanoma is an aggressive intraocular malignancy that often exhibits low immunogenicity. Metastatic uveal melanoma samples frequently exhibit monosomy 3 or BAP1 deficiency. In this study, we used bioinformatic methods to investigate the immune infiltration of uveal melanoma samples in public datasets. We first performed Gene Set Enrichment/Variation Analyses to detect immunological pathways that are altered in tumors with monosomy 3 or BAP1 deficiency. We then conducted an unsupervised clustering analysis to identify distinct immunologic molecular subtypes of uveal melanoma. We used CIBERSORT and ESTIMATE with RNA-seq data from The Cancer Genome Atlas and the GSE22138 microarray dataset to determine the samplelevel immune subpopulations and immune scores of uveal melanoma samples. The Kaplan-Meier method and log-rank test were used to assess the prognostic value of particular immune cells and genes in uveal melanoma samples. Through these approaches, we discovered uveal melanoma-specific immunologic features, which may provide new insights into the tumor microenvironment and enhance the development of immunotherapies in the future.

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Section: Discussionmentioning

confidence: 99%

Immunological analyses reveal an immune subtype of uveal melanoma with a poor prognosis

Pan

Liu

Cui

et al. 2020

Aging

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“…GNAQ, GNA11, CYSLTR2, and PLCB4 somatic mutations are crucial in early UM development but are not related to metastatic behavior or a bad prognosis ( 6 ). Therefore, these mutations are currently considered as precursor events in UM development, with the need for a “second hit” to complete the malignant transformation ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Expression of P16INK4a in Uveal Melanoma: New Perspectives

et al. 2020

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Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite sharing the name and similar morphological features with cutaneous melanoma (CM), it is an entirely different neoplasia with a particular genetic background and clinical behavior. CDKN2A is a gene located at chromosome 9p21, encoding for P16INK4a and P14(ARF) proteins, whose role as a tumor suppressor has been clearly defined in many malignant tumors. CDKN2A frequently presents germline mutations in familial CM and epigenetic downregulation in a considerable percentage of sporadic CM. It has been hypothesized that CDKN2A alterations are early events in CM development, playing a central role in the malignant transformation of melanocytes. Alterations of the CDKN2A gene reduce the expression of P16INK4a in most CM subtypes. Immunohistochemical evaluation of P16INK4a is currently used, in association with Ki67 and HMB45, in pathology practice to discriminate between dysplastic nevi and melanoma. On the other hand, CKDN2A is rarely mutated in UM, and the immunohistochemical expression of P16INK4a has only been reported in small case series. We tested P16INK4a expression on paraffin-embedded tissue sections from 9 tissue microarrays (TMAs), built with 2 mm cores derived from 133 uveal melanoma FFPE blocks, collected from 1990 to 2018, and from selected paraffin-blocks of 3 UM liver metastases. The immunohistochemical expression of P16INK4a was assessed with a visual evaluation by light microscopy and then with a digital approach. Both approaches, with an acceptable concordance rate, revealed P16INK4a expression in a large proportion of UM cases and all liver metastases, opening new possibilities of using it in the differential diagnosis between cutaneous and uveal melanoma metastases in cases of unknown primary tumor or patients with two different primary melanomas.

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“…Three mutations of Gly48 have been previously identified [6,[14][15][16]. p.Gly48Val was found in cherry hemangiomas in the presence of a hotspot mutation in position Gln209, and no effect was attributed to it [17].…”

Section: Modelling Analysismentioning

confidence: 99%

Trametinib Induces the Stabilization of a Dual GNAQ p.Gly48Leu- and FGFR4 p.Cys172Gly-Mutated Uveal Melanoma. The Role of Molecular Modelling in Personalized Oncology

Krebs¹,

Gérard

Wicky

et al. 2020

IJMS

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We report a case of an uveal melanoma patient with GNAQ p.Gly48Leu who responded to MEK inhibition. At the time of the molecular analysis, the pathogenicity of the mutation was unknown. A tridimensional structural analysis showed that Gαq can adopt active and inactive conformations that lead to substantial changes, involving three important switch regions. Our molecular modelling study predicted that GNAQ p.Gly48Leu introduces new favorable interactions in its active conformation, whereas little or no impact is expected in its inactive form. This strongly suggests that GNAQ p.Gly48Leu is a possible tumor-activating driver mutation, consequently triggering the MEK pathway. In addition, we also found an FGFR4 p.Cys172Gly mutation, which was predicted by molecular modelling analysis to lead to a gain of function by impacting the Ig-like domain 2 folding, which is involved in FGF binding and increases the stability of the homodimer. Based on these analyses, the patient received the MEK inhibitor trametinib with a lasting clinical benefit. This work highlights the importance of molecular modelling for personalized oncology.

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Molecular Characteristics of Uveal Melanoma: Insights from the Cancer Genome Atlas (TCGA) Project

Cited by 60 publications

References 74 publications

Immunological analyses reveal an immune subtype of uveal melanoma with a poor prognosis

Immunological analyses reveal an immune subtype of uveal melanoma with a poor prognosis

Expression of P16INK4a in Uveal Melanoma: New Perspectives

Trametinib Induces the Stabilization of a Dual GNAQ p.Gly48Leu- and FGFR4 p.Cys172Gly-Mutated Uveal Melanoma. The Role of Molecular Modelling in Personalized Oncology

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