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.