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GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma
E Livingstone1, A Zaremba1, S Horn1,2
1Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.
Background:
GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma.
Objectives:
To characterize these tumours in terms of clinical behaviour and genetic characteristics.
Methods:
Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden.
Results:
We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%).
Conclusions:
Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented. GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma. What does this study add? GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma. GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma. What is the translational message? Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma. As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed. Linked Comment: Rafei-Shamsabadi. Br J Dermatol 2020; 183:806-807.
Insights
GNAQ/11 mutant nonuveal melanomas are a distinct subtype with unique clinical and genetic features. These rare melanomas show poor response to current therapies, necessitating novel treatment strategies.
Area of Science:
- Oncology
- Dermatology
- Genetics
Background:
- GNAQ and GNA11 mutations define a rare nonuveal melanoma subgroup, sharing genetic similarities with uveal melanoma.
- Limited characterization exists for the clinical behavior and genetic landscape of these GNAQ/11 mutant nonuveal melanomas.
Purpose of the Study:
- To comprehensively characterize GNAQ/11 mutant nonuveal melanomas.
- To investigate their clinical behavior, metastatic patterns, and genetic alterations.
- To assess their response to existing treatment modalities, including immunotherapy.
Main Methods:
- Retrospective analysis of 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma.
- Data collection included patient, tumor, and treatment characteristics.
- Targeted sequencing for tumor mutational burden, immunohistochemistry for PD-L1 and BAP1, and comparative analysis with existing melanoma datasets.
Main Results:
- GNAQ/11 mutant nonuveal melanomas exhibit lower tumor mutational burden and fewer UV-signature mutations than cutaneous melanomas.
- Frequent lymphatic metastasis observed, contrasting with uveal melanoma.
- Poor objective response to immunotherapy (1/10 partial response), with no clear prognostic association for concurrent SF3B1, EIF1AX, or BAP1 mutations.
Conclusions:
- GNAQ/11 mutant nonuveal melanomas represent a clinically and genetically distinct subtype.
- Their metastatic behavior resembles cutaneous melanoma, but they possess a unique mutational profile.
- Urgent need for novel therapeutic strategies due to poor response to current treatments.
