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. 2022 Apr 22;14(9):2090.
doi: 10.3390/cancers14092090.

Genetic and Clinical Characteristics of ARID1A Mutated Melanoma Reveal High Tumor Mutational Load without Implications on Patient Survival

Carl Maximilian Thielmann  1   2 , Johanna Matull  1   2 , Sebastian Roth  3 , Jan-Malte Placke  1   2 , Eleftheria Chorti  1   2 , Anne Zaremba  1   2 , Georg Lodde  1   2 , Philipp Jansen  1   2   4 , Frederik Krefting  1   2 , Julia Kretz  1   2 , Inga Möller  1   2 , Antje Sucker  1   2 , Annette Paschen  1   2 , Elisabeth Livingstone  1   2 , Lisa Zimmer  1   2 , Selma Ugurel  1   2 , Dirk Schadendorf  1   2 , Eva Hadaschik  1   2 , Klaus G Griewank  1   2
Affiliations

Genetic and Clinical Characteristics of ARID1A Mutated Melanoma Reveal High Tumor Mutational Load without Implications on Patient Survival

Carl Maximilian Thielmann et al. Cancers (Basel). .

Abstract

(1) Background: Melanoma has the highest mortality of all cutaneous tumors, despite recent treatment advances. Many relevant genetic events have been identified in the last decade, including recurrent ARID1A mutations, which in various tumors have been associated with improved outcomes to immunotherapy. (2) Methods: Retrospective analysis of 116 melanoma samples harboring ARID1A mutations. Assessment of clinical and genetic characteristics was performed as well as correlations with treatment outcome applying Kaplan-Meier (log-rank test), Fisher's exact and Chi-squared tests. (3) Results: The majority of ARID1A mutations were in cutaneous and occult melanoma. ARID1A mutated samples had a higher number of mutations than ARID1A wild-type samples and harbored UV-mutations. A male predominance was observed. Many samples also harbored NF1 mutations. No apparent differences were noted between samples harboring genetically inactivating (frame-shift or nonsense) mutations and samples with other mutations. No differences in survival or response to immunotherapy of patients with ARID1A mutant melanoma were observed. (4) Conclusions: ARID1A mutations primarily occur in cutaneous melanomas with a higher mutation burden. In contrast to findings in other tumors, our data does not support ARID1A mutations being a biomarker of favorable response to immunotherapies in melanoma. Larger prospective studies would still be warranted.

Keywords: ARID1A; melanoma; mutation profiling.

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Conflict of interest statement

C.M.T.: No relevant conflicts of interest. J.M.: Declares travel support from Bristol Myers Squibb, Novartis and Sun Pharmaceutical Industries. S.R.: No relevant conflicts of interest. J.M.P.: Served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis and received travel support from Bristol-Myers Squibb, Novartis and Therakos. E.C.: No relevant conflicts of interest. A.Z.: Declares travel support from Novartis, Sanofi Grenzyme, and Bristol-Myers Squibb, outside the submitted work. G.L.: Declares travel support from Sun Pharma, outside the submitted work. P.J.: No relevant conflicts of interest. F.K.: Declares travel support from Novartis, outside the submitted work. J.K.: No relevant conflicts of interest. I.M.: No relevant conflicts of interest. A.S.: No relevant conflicts of interest. A.P.: Reports research grant support from BMS and Merck Sharp & Dohme. E.L.: Served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Sanofi, Sunpharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. L.Z.: 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. S.U.: Declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme, outside the submitted work. D.S.: 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. E.H.: No relevant conflicts of interest. K.G.: No relevant conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Mutation analysis in ARID1A mutated melanoma. ARID1A mutated melanoma harbored more mutations compared to ARID1A-wt melanoma (A). ARID1A mutated melanomas exhibit a higher mutation number compared to other melanoma subtypes (B). Within the group of ARID1A mutated melanomas, NF1 mutant samples exhibit the highest number of mutations (C). PD-L1 expression levels did not differ between samples with inactivating and other ARID1A mutations. The rate of PD-L1 positive tumors was comparable between the groups (D,E). Statistical tests performed are Mann–Whitney U tests. Data are shown as mean ± SEM. **** p < 0.0001. ns: no significant; p < 0.0001.
Figure 2
Figure 2
Survival Analysis of ARID1A mutated melanoma. Overall survival of ARID1A mutated stage IV melanoma (A). No difference in progression-free or overall survival was noticed comparing patients who received either immune checkpoint inhibitors or targeted therapies as their first-line non-adjuvant therapies (B,C). Patients with inactivating ARID1A mutations did not differ in progression-free and overall survival compared to other mutations (D,E).
Figure 3
Figure 3
Oncoplot of ARID1A mutated melanoma. Mutation distribution in ARID1A mutated 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 ARID1A. Lollipop mutation graph demonstrating the distribution of mutations. Missense mutations are demonstrated in green, inactivating (Nonsense or frame-shift mutations) in black, in frame frameshift mutations in brown.
See this image and copyright information in PMC

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