Unmasking the “targetless” illusion: branched clonal evolution of TERT and KIT in acral melanoma revealed by sequential multi-site biopsies- a case report

Tumor clonal evolution and spatiotemporal heterogeneity are key drivers of therapeutic resistance in melanoma, often driven by selection pressures generated by systemic therapy. Genetic testing plays a key role in guiding targeted therapies, but a single biopsy may not fully reflect the mutational landscape. This paper reports a case of metastatic acral melanoma that demonstrated dynamic branching clonal evolution under systemic therapeutic stress. The patient first underwent genetic testing in 2022. A 168-gene panel performed on a newly developed inguinal lymph node metastasis revealed only a TERT promoter mutation (c.-124C>T), with no KIT mutation detected. Disease progression despite multiple rounds of cytotoxic chemotherapy, antiangiogenic therapy, and immunotherapy. A 10-gene panel testing on the newly developed abdominal skin metastasis in 2024 revealed a rare KIT exon 18 mutation (p.Ala829Pro). However, the panel did not include the TERT gene. Then our retrospective single-gene testing of this abdominal skin metastasis confirmed the presence of concurrent TERT mutations. Retrospective testing of the primary acral lesion from 2019 showed that TERT and KIT mutations coexisted in a subclonal pattern. The variant allele frequency of KIT in the advanced cutaneous metastasis increased significantly, suggesting the possible occurrence allelic imbalance at the KIT gene locus. This case demonstrates that the KIT -mutant subclone in the advanced cutaneous metastasis was not newly acquired, but rather a pre-existing cell population that was selected for through a stringent therapeutic bottleneck. The study also showed the inherent resistance of the KIT p.Ala829Pro mutation to imatinib, explaining the failure of subsequent treatment. This study highlights the significant spatial and temporal heterogeneity of acral melanoma and underscores the critical importance of serial biopsies in accurately capturing clonal dynamics and guiding precision oncology therapy.