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

SIMPLE SUMMARY: Melanoma is a highly malignant skin cancer with the highest mortality of all cutaneous tumors. Relevant genetic events have been identified, which shape the tumor and also the response to treatment. Recurrent ARID1A mutations have been identified, which are associated with improved outcomes to immune checkpoint inhibition in various tumors. Not much was known about the role of ARID1A mutations in melanoma to date. We investigated the largest cohort of ARID1A mutated melanoma to date and were able to show that despite a high mutational load the described beneficial treatment response is not apparent in melanoma. 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.