Melanocytic neoplasms have been genetically characterized in detail during the last decade.
Recurrent CTNNB1 exon 3 mutations have been recognized in the distinct group of melanocytic
tumors showing ...deep penetrating nevus-like morphology. In addition, they have been identified
in 1–2% of advanced melanoma. Performing a detailed genetic analysis of difficult-to-classify nevi
and melanomas with CTNNB1 mutations, we found that benign tumors (nevi) show characteristic morphological, genetic and epigenetic traits, which distinguish them from other nevi and
melanoma. Malignant CTNNB1-mutant tumors (melanomas) demonstrated a different genetic profile,
instead grouping clearly with other non-CTNNB1 melanomas in methylation assays. To further
evaluate the role of CTNNB1 mutations in melanoma, we assessed a large cohort of clinically sequenced melanomas, identifying 38 tumors with CTNNB1 exon 3 mutations, including recurrent S45
(n = 13, 34%), G34 (n = 5, 13%), and S27 (n = 5, 13%) mutations. Locations and histological subtype of
CTNNB1-mutated melanoma varied; none were reported as showing deep penetrating nevus-like
morphology. The most frequent concurrent activating mutations were BRAF V600 (n = 21, 55%) and
NRAS Q61 (n = 13, 34%). In our cohort, four of seven (58%) and one of nine (11%) patients treated with targeted therapy (BRAF and MEK Inhibitors) or immune-checkpoint therapy, respectively, showed
disease control (partial response or stable disease). In summary, CTNNB1 mutations are associated
with a unique melanocytic tumor type in benign tumors (nevi), which can be applied in a diagnostic
setting. In advanced disease, no clear characteristics distinguishing CTNNB1-mutant from other
melanomas were observed; however, studies of larger, optimally prospective, cohorts are warranted.
