TY  - JOUR
A1  - Maurus, K.
A1  - Kosnopfel, C.
A1  - Kneitz, H.
A1  - Appenzeller, S.
A1  - Schrama, D.
A1  - Glutsch, V.
A1  - Roth, S.
A1  - Gerhard-Hartmann, E.
A1  - Rosenfeldt, M.
A1  - Möhrmann, L.
A1  - Fröhlich, M.
A1  - Hübschmann, D.
A1  - Stenzinger, A.
A1  - Glimm, H.
A1  - Fröhling, S.
A1  - Goebeler, M.
A1  - Rosenwald, A.
A1  - Kutzner, H.
A1  - Schilling, B.
T1  - Cutaneous epithelioid haemangiomas show somatic mutations in the mitogen-activated protein kinase pathway
JF  - British Journal of Dermatology
N2  - Background
Epithelioid haemangioma (EH) arising from the skin is a benign vascular tumour with marked inflammatory cell infiltration, which exhibits a high tendency to persist and frequently recurs after resection. So far, the underlying pathogenesis is largely elusive.

Objectives
To identify genetic alterations by next-generation sequencing and/or droplet digital polymerase chain reaction (ddPCR) in cutaneous EH.

Methods
DNA and RNA from an EH lesion of an index patient were subjected to whole-genome and RNA sequencing. Multiplex PCR-based panel sequencing of genomic DNA isolated from archival formalin-fixed paraffin-embedded tissue of 18 patients with cutaneous EH was performed. ddPCR was used to confirm mutations.

Results
We identified somatic mutations in genes of the mitogen-activated protein kinase (MAPK) pathway (MAP2K1 and KRAS) in cutaneous EH biopsies. By ddPCR we could confirm the recurrent presence of activating, low-frequency mutations affecting MAP2K1. In total, nine out of 18 patients analysed showed activating MAPK pathway mutations, which were mutually exclusive. Comparative analysis of tissue areas enriched for lymphatic infiltrate or aberrant endothelial cells, respectively, revealed an association of these mutations with the presence of endothelial cells.

Conclusions
Taken together, our data suggest that EH shows somatic mutations in genes of the MAPK pathway which might contribute to the formation of this benign tumour.
KW  - protein kinase pathway
KW  - Background Epithelioid haemangioma
KW  - somatic mutations
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258333
VL  - 186
IS  - 3
ER  - 
TY  - JOUR
A1  - Livingstone, E.
A1  - Zaremba, A.
A1  - Horn, S.
A1  - Ugurel, S.
A1  - Casalini, B.
A1  - Schlaak, M.
A1  - Hassel, J.C.
A1  - Herbst, R.
A1  - Utikal, J.S.
A1  - Weide, B.
A1  - Gutzmer, R.
A1  - Meier, F.
A1  - Koelsche, C.
A1  - Hadaschik, E.
A1  - Sucker, A.
A1  - Reis, H.
A1  - Merkelbach‐Bruse, S.
A1  - Siewert, M.
A1  - Sahm, F.
A1  - von Deimling, A.
A1  - Cosgarea, I.
A1  - Zimmer, L.
A1  - Schadendorf, D.
A1  - Schilling, B.
A1  - Griewank, K.G.
T1  - GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma
JF  - British Journal of Dermatology
N2  - 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.
KW  - melanoma
KW  - GNAQ
KW  - GNA11
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215434
VL  - 183
IS  - 5
SP  - 928
EP  - 939
ER  - 
TY  - JOUR
A1  - Weber, J.
A1  - Glutsch, V.
A1  - Geissinger, E.
A1  - Haug, L.
A1  - Lock, J.F.
A1  - Schneider, F.
A1  - Kneitz, H.
A1  - Goebeler, M.
A1  - Schilling, B.
A1  - Gesierich, A.
T1  - Neoadjuvant immunotherapy with combined ipilimumab and nivolumab in patients with melanoma with primary or in transit disease
JF  - British Journal of Dermatology
N2  - The introduction of new therapeutic agents has revolutionized the treatment of metastatic melanoma. The approval of adjuvant anti‐programmed death‐1 monotherapy with nivolumab or pembrolizumab, and dabrafenib plus trametinib has recently set a new landmark in the treatment of stage III melanoma. Now, clinical trials have shown that immune checkpoint blockade can be performed in a neoadjuvant setting, an approach established as a standard therapeutic approach for other tumour entities such as breast cancer. Recent studies suggest that a pathological response achieved by neoadjuvant immunotherapy is associated with long‐term tumour control and that short neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. Most recently, neoadjuvant ipilimumab plus nivolumab in stage III melanoma was reported. With two courses of dose‐optimized ipilimumab (1 mg kg−1) combined with nivolumab (3 mg kg−1), pathological responses were observed in 77% of patients, while only 20% of patients experienced grade 3 or 4 adverse events. However, the neoadjuvant trials employing combined immune checkpoint blockade conducted so far have excluded patients with in transit metastases, a common finding in stage III melanoma. Here we report four patients with in transit metastases or an advanced primary tumour who have been treated with neoadjuvant ipilimumab plus nivolumab according to the OpACIN‐neo trial scheme (arm B). All patients achieved radiological disease control and a pathological response. None of the patients has relapsed so far.
KW  - Immunotherapy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213520
VL  - 183
IS  - 3
ER  -