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. 2024 Jun 5:15:1383125.
doi: 10.3389/fimmu.2024.1383125. eCollection 2024.

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

Johanna Matull  1   2 , Jan-Malte Placke  1 , Georg Lodde  1 , Anne Zaremba  1 , Jochen Utikal  3   4   5 , Patrick Terheyden  6 , Claudia Pföhler  7 , Rudolf Herbst  8 , Alexander Kreuter  2 , Julia Welzel  9 , Julia Kretz  1 , Inga Möller  1 , Antje Sucker  1 , Annette Paschen  1 , Elisabeth Livingstone  1 , Lisa Zimmer  1 , Eva Hadaschik  1 , Selma Ugurel  1 , Dirk Schadendorf  1   10   11 , Carl Maximilian Thielmann #  1 , Klaus Georg Griewank #  1
Affiliations

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

Johanna Matull et al. Front Immunol. .

Abstract

Background: Screening for gene mutations has become routine clinical practice across numerous tumor entities, including melanoma. BAP1 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.

Methods: A retrospective analysis of all melanomas sequenced in our department from 2014-2022 (n=2650) was conducted to identify BAP1 mutated samples. Assessment of clinical and genetic characteristics was performed as well as correlations with treatment outcome.

Results: BAP1 mutations were identified in 129 cases and distributed across the entire gene without any apparent hot spots. Inactivating BAP1 mutations were more prevalent in uveal (55%) compared to non-uveal (17%) melanomas. Non-uveal BAP1 mutated melanomas frequently exhibited UV-signature mutations and had a significantly higher mutation load than uveal melanomas. GNAQ and GNA11 mutations were common in uveal melanomas, while MAP-Kinase mutations were frequent in non-uveal melanomas with NF1, BRAF V600 and NRAS 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 BAP1 mutations.

Conclusion: In contrast to uveal melanomas, where BAP1 mutations serve as a significant prognostic indicator of an unfavorable outcome, BAP1 mutations in non-uveal melanomas are primarily considered passenger mutations and do not appear to be relevant from a prognostic or therapeutic perspective.

Keywords: BAP1; immunotherapy; mutation profiling; non-uveal melanoma; uveal melanoma.

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Conflict of interest statement

JM: Declares travel support from Bristol Myers Squibb, Novartis and Sun Pharmaceutical Industries, outside the submitted work. J-MP: served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis, Sanofi and received travel support from Bristol-Myers Squibb, Novartis, Pierre Fabre and Therakos, outside the submitted work. GL: Declares travel support from Sun Pharma, outside the submitted work. AZ: Declares travel support from Novartis, Sanofi Grenzyme, and Bristol-Myers Squibb, outside the submitted work. JU: Is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. PT: served as consultant and/or received honoraria form Almirall, Bristol Myers Squibb, Biofrontera, Curevac, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Roche, Sanofi, 4SC, and travel support from Bristol Myers Squibb outside the submitted work. CP: Received honoraria speaker honoraria and advisory-board honoraria and travel support from BMS, MSD, Novartis, Merck Serono, Pierre Fabre, Sunpharma, AbbVie, LEO, and Kyona Kirin, outside the submitted work. RH: Is an employee of Helios Kliniken Erfurt GmbH. JW: Received honoraria and travel support from Almirall, Bristol Myers Squibb, Novartis, Pierre Fabre and Merck Sharp & Dohme, outside the submitted work. EL: Served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, Sunpharma, Takeda and travel support from Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. LZ: Served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol- Myers Squibb, Amgen, Pierre-Fabre, Sunpharma and Novartis, outside the submitted work. SU: Research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma, outside the submitted work. DS: Reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from SunPharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Characteristics of BAP1mut melanoma. Distribution of activating gene mutations in BAP1mut non-uveal (left) and uveal (right) melanoma tumor samples (A). Left: BAP1mut melanoma harbored more mutations than BAP1wt melanoma. Middle: Within the group of BAP1mut melanoma, non-uveal tumors exhibited higher mutation numbers than tumors of uveal origin. Right: Non-uveal BAP1mut tumors from cutaneous sites showed the highest number of mutations compared with tumors of uveal origin and mucosal, meningeal or occult origin (subsumed as “other”) (B). Uveal BAP1mut tumor samples exhibited the lowest amount of C>T substitutions compared to both non-uveal BAP1mut and BAP1wt melanomas (C). Statistical tests were performed using Welch’s t test and Dunnett’s test. Data is shown as mean ± SEM. *p < 0.05, ****p < 0.0001.
Figure 2
Figure 2
Lollipop mutation graph demonstrates the distribution of mutations throughout the BAP1 gene with missense mutations shown in green, inactivating (Nonsense or frame-shift mutations) in black, and frameshift mutations in brown.
Figure 3
Figure 3
Mutation distribution in BAP1mut non-uveal melanoma. Green: mutations known or assumed to be activating. Red: loss of function mutations. Blue: known activating mutations in the TERT promoter region.
Figure 4
Figure 4
Mutation distribution in BAP1mut uveal melanoma. Green: mutations known or assumed to be activating. Red: loss of function mutations.
Figure 5
Figure 5
Patients with stage IV BAP1mut non-uveal melanoma (n=73) did not show a difference in overall survival compared to patients with stage IV BAP1mut uveal melanoma (n=8) (A). Survival rates of BAP1mut non-uveal melanoma patients receiving immunotherapy as first non-adjuvant therapy compared to those receiving targeted therapies showed no significant difference in either progression-free or overall survival (B, C). Patients with inactivating BAP1 mutations did not differ in overall survival compared to those with other mutation types (D).
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