Constitutive activation of Gαq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK. Protein kinase C (PKC) has been implicated as a link, but the ...mechanistic details remained unclear. We identified PKC δ and ɛ as required and sufficient to activate MAPK in GNAQ mutant melanomas. MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM. RasGRP3 activation occurs via PKC δ- and ɛ-dependent phosphorylation and PKC-independent, DAG-mediated membrane recruitment, possibly explaining the limited effect of PKC inhibitors to durably suppress MAPK in UM. The findings nominate RasGRP3 as a therapeutic target for cancers driven by oncogenic GNAQ/11.
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•PKC δ/ɛ mediate ERK activation in uveal melanoma with Gαq pathway mutations•The RAS exchange factor RasGRP3 is a critical module for ERK activation•PKC δ, PKC ɛ, and RasGRP3 are novel therapeutic targets for uveal melanoma
Chen et al. find that Ras is required for GNAQ-mediated MAPK activation and identify PKC δ,ɛ and RasGRP3 as components of a signaling module necessary and sufficient to activate the Ras/MAPK pathway in GNAQ mutant uveal melanoma (UM). RasGRP3 is selectively overexpressed in response to GNAQ/11 mutations in UM.
Summary
The eye is a rare site for the development of malignant lymphoma. Based on cell type and involved intraocular structures, which as a whole represent an immune‐privileged site, several ...subtypes of primary intraocular lymphoma need to be discerned. Primary vitreoretinal lymphoma (PVRL), the most common form, is an aggressive B‐cell malignancy and considered a subtype of primary central nervous system (CNS) lymphoma. Ocular symptoms are non‐specific and often mimic uveitis, frequently resulting in delayed diagnosis. Bilateral ocular involvement and dissemination/relapse in the CNS are common. Diagnosis of PVRL is usually based on the analysis of vitreous biopsy material. In addition to cytological and immunocytochemical examination, measurements of cytokine levels and molecular determination of B‐cell clonality and recurrent mutations increase the diagnostic yield. Both systemic chemotherapy and exclusively local treatment, including ocular radiotherapy and intravitreal chemotherapy, are successful approaches for the management of PVRL, although it is currently not predictable which patients require systemic treatment in order to avoid cerebral dissemination, a complication associated with a considerably worse prognosis.
Vitreoretinal diffuse large B-cell lymphoma is a rare disorder, occurring as primary ocular disease or as secondary involvement by primary central nervous system lymphoma. It is usually diagnosed by ...cytologic, immunocytochemical, and molecular examination of vitreous aspirates. However, distinguishing vitreoretinal diffuse large B-cell lymphoma from uveitis remains difficult, and clonality analysis may be either unsuccessful or misleading. Diffuse large B-cell lymphoma arising in immune-privileged sites (eg, the central nervous system) shows a high frequency of MYD88 mutations. Therefore, we retrospectively assessed the frequency of MYD88 mutations in vitreoretinal lymphoma (VRL) and their diagnostic potential in 75 vitrectomy samples of 69 patients, and validated our results in a separate cohort (n = 21). MYD88 mutations were identified in 20 of 29 (69%) clinically, histologically, and molecularly confirmed VRL, including 6 cases of the test cohort initially diagnosed as reactive (3/6) or suspicious (3/6) for lymphoma. MYD88 mutations, especially L265P, are very frequent in VRL and their detection significantly improves the diagnostic yield of vitrectomy specimens.
•MYD88 mutation analysis significantly improves the detection rate of vitreoretinal B-cell lymphoma.•The high frequency of MYD88 mutations in primary VRL provides further evidence that VRL and primary CNS lymphoma represent the same entity.
The orbit can harbor mass lesions of various cellular origins. The symptoms vary considerably according to the nature, location, and extent of the disease and include common signs of proptosis, globe ...displacement, eyelid swelling, and restricted eye motility. Although radiological imaging tools are improving, with each imaging pattern having its own differential diagnosis, orbital mass lesions often pose a diagnostic challenge. To provide an accurate, specific, and sufficiently comprehensive diagnosis, to optimize clinical management and estimate prognosis, pathological examination of a tissue biopsy is essential. Diagnostic orbital tissue biopsy is obtained through a minimally invasive orbitotomy procedure or, in selected cases, fine needle aspiration. The outcome of successful biopsy, however, is centered on its representativeness, processing, and interpretation. Owing to the often small volume of the orbital biopsies, artifacts in the specimens should be limited by careful peroperative tissue handling, fixation, processing, and storage. Some orbital lesions can be characterized on the basis of cytomorphology alone, whereas others need ancillary molecular testing to render the most reliable diagnosis of therapeutic, prognostic, and predictive value. Herein, we review the diagnostic algorithm for orbital mass lesions, using clinical, radiological, and pathological recommendations, and discuss the methods and potential pitfalls in orbital tissue biopsy acquisition and analysis.
Metastasis from uveal melanoma occurs almost exclusively with tumors showing chromosome 3 loss. We used multiplex ligation-dependent probe amplification (MLPA) to detect chromosome 1p, 3, 6p, 6q, 8p, ...and 8q abnormalities in uveal melanomas. The purpose of this study was to correlate our MLPA results with other risk factors and metastatic death.
Patients were included if they had a uveal melanoma involving choroid. Correlations between baseline risk factors were analyzed using the chi-square test (without Yates's adjustment) and the Mann-Whitney test, with log-rank analysis for associations with metastatic death.
The patients (194 female; 258 male) had a median age of 59.4 years and a median follow-up of 1.89 years. MLPA abnormalities occurred in a wide variety of combinations. Ten-year disease-specific mortality was 0% in 133 tumors with no chromosome 3 loss, 55% in tumors with chromosome 3 loss but no chromosome 8q gain, and 71% in 168 tumors showing combined chromosome 3 loss and 8q gain. In tumors with both these abnormalities, epithelioid melanoma cytomorphology, closed loops, and high mitotic rate correlated with poor survival as did lack of chromosome 6p gain.
These results support the use of MLPA for routine clinical prognostication, especially if the genetic data are considered together with clinical and histologic risk factors. We showed a wide variety of MLPA results, which suggests that chromosomal abnormalities in uveal melanoma accumulate in a variable sequence.
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