Melanomas in Blue Nevi Lack TERT Promoter Mutations and Carry Uniformly Low Tumour Mutational Burden

Original abstract

Melanoma arising in blue nevus (MBN) is a rare melanoma subtype with distinct molecular characteristics and biological behaviors compared to other cutaneous melanomas. However, limited data exists on the frequency of TERT promoter mutations (TPMs), tumor mutational burden (TMB), and molecular alterations beyond the well-known GNAQ, GNA11, SF3B1, and BAP1 mutations. Here, we provide a comprehensive clinicopathologic and molecular analysis of 11 MBNs from a single tertiary hospital. MBNs were consistently dermal-based with expansile vertical growth, exhibiting substantial Breslow thickness (median: 8.4 mm). At initial diagnosis, they frequently showed microscopic satellitosis (MS) (36%), sentinel lymph node involvement (45%), and/or synchronous metastasis (9%), all contributing to high initial pathological staging. Molecularly, all MBNs harbored either GNA11 (64%) or GNAQ (36%) mutations, with a subset additionally displaying SF3B1 (29%) or BAP1 (43%) mutations. Unique gene amplifications of RUNX1T1 (8q21.3) and SOX17 (8q11.23) and novel missense mutations in TOPBP1 and MAP2K1 were identified in individual cases. Notably, none of the MBNs exhibited TPMs, and the tumors had a consistently low TMB of 1 mutation/Mb, distinct from other melanoma subtypes, including deep penetrating nevus-like melanomas that morphologically mimic MBNs. Over a median follow-up of 36 months (range: 3-132 months), 73% developed distant metastases, and 55% died from disease. The presence of MS appeared to correlate with worse clinical outcomes, as 67% of patients with MS died, compared to none without. Our findings expand the recognized molecular diversity of MBNs and provide insights into their biological behaviors, underscoring the clinical significance of identifying potential prognostic factors.