AUTHOR=Matull Johanna , Placke Jan-Malte , Lodde Georg , Zaremba Anne , Utikal Jochen , Terheyden Patrick , Pföhler Claudia , Herbst Rudolf , Kreuter Alexander , Welzel Julia , Kretz Julia , Möller Inga , Sucker Antje , Paschen Annette , Livingstone Elisabeth , Zimmer Lisa , Hadaschik Eva , Ugurel Selma , Schadendorf Dirk , Thielmann Carl Maximilian , Griewank Klaus Georg 

TITLE=Clinical and genetic characteristics of BAP1-mutated non-uveal and uveal melanoma

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1383125

DOI=10.3389/fimmu.2024.1383125

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Screening for gene mutations has become routine clinical practice across numerous tumor entities, including melanoma. <italic>BAP1</italic> gene mutations have been identified in various tumor types and acknowledged as a critical event in metastatic uveal melanoma, but their role in non-uveal melanoma remains inadequately characterized.</p></sec><sec><title>Methods</title><p>A retrospective analysis of all melanomas sequenced in our department from 2014–2022 (n=2650) was conducted to identify <italic>BAP1</italic> mutated samples. Assessment of clinical and genetic characteristics was performed as well as correlations with treatment outcome.</p></sec><sec><title>Results</title><p><italic>BAP1</italic> mutations were identified in 129 cases and distributed across the entire gene without any apparent hot spots. Inactivating <italic>BAP1</italic> mutations were more prevalent in uveal (55%) compared to non-uveal (17%) melanomas. Non-uveal <italic>BAP1</italic> mutated melanomas frequently exhibited UV-signature mutations and had a significantly higher mutation load than uveal melanomas. <italic>GNAQ</italic> and <italic>GNA11</italic> mutations were common in uveal melanomas, while MAP-Kinase mutations were frequent in non-uveal melanomas with <italic>NF1</italic>, <italic>BRAF</italic> V600 and <italic>NRAS</italic> Q61 mutations occurring in decreasing frequency, consistent with a strong UV association. Survival outcomes did not differ among non-uveal melanoma patients based on whether they received targeted or immune checkpoint therapy, or if their tumors harbored inactivating <italic>BAP1</italic> mutations.</p></sec><sec><title>Conclusion</title><p>In contrast to uveal melanomas, where <italic>BAP1</italic> mutations serve as a significant prognostic indicator of an unfavorable outcome, <italic>BAP1</italic> mutations in non-uveal melanomas are primarily considered passenger mutations and do not appear to be relevant from a prognostic or therapeutic perspective.</p></sec>