Abstract: Isocitrate dehydrogenase 1 (IDH1) mutations are well-established oncogenic drivers in several malignancies, including gliomas and hematologic neoplasms, but are rarely reported in melanoma and remain poorly characterized in this tumor type. Their clinicopathological and molecular significance in cutaneous melanoma is not well-defined. We retrospectively analyzed 9 cases of cutaneous melanoma harboring IDH1 mutations identified by next-generation sequencing from a larger institutional cohort. Clinicopathological characteristics, immunohistochemical profiles (including p16, PRAME, Ki-67, and PD-L1), and associated molecular alterations were evaluated. Eight tumors carried the pathogenic IDH1 p.R132C mutation and one harbored p . V178I . Most cases corresponded to nodular melanomas with epithelioid morphology, increased Breslow thickness (median 2.87 mm), high mitotic activity, and frequent ulceration. Tumor-infiltrating lymphocytes were weak or absent in most tumors. All cases expressed S100 and Melan-A; PRAME was strongly positive in 6 cases, while partial or complete loss of p16 expression was observed in all tumors. PD-L1 expression (tumor proportion score 1%–49%) was detected in 3 cases. Co-occurring mutations in the MAPK pathway were identified in 8 tumors, and 5 cases also harbored TERT promoter mutations (c.-146C>T, C228T). Comparable variant allele frequencies of IDH1 and associated mutations suggest an early oncogenic role. IDH1-mutated melanomas represent a rare molecular subset frequently associated, in this limited series, with established high-risk clinicopathological features. The recurrent coexistence of IDH1 mutations with MAPK pathway and TERT promoter alterations supports a potential cooperative role within melanoma oncogenesis. These findings are descriptive and hypothesis-generating, and further studies with larger cohorts are required to clarify the biological and clinical relevance of IDH1 mutations in melanoma.
Carbonell-Zamorano et al. (Fri,) studied this question.