Evaluation of clonality in lentigo maligna

Lentigo maligna (LM), a type of in situ melanoma, has a high rate of local recurrence after surgical resection. Although recurrences might represent inadequately excised incident LMs, apparent recurrences could be new primary LMs developing from distinct melanocytic clones in the same UVR-damaged anatomical region. Because distinguishing these possibilities has implications for patient management, we tested genetic relationships between incident and recurrent LMs. Incident LMs with histologically clear margins and their recurrent LMs and invasive LM melanomas were laser microdissected for DNA extraction. Tumor and matched germline DNA underwent whole-exome sequencing. Clonal relationships between incident and recurrent LMs were tested by elucidating and tracking clones within and across samples. Seven incident LMs with recurrent LM and 4 with recurrent LM melanoma were sequenced. LM/LM melanomas had a high mutational burden, a predominant UVR signature, copy number alterations, and defects in DNA repair and cell-cycle checkpoint regulator genes. All incident LMs were clonally related to their postoperative local recurrences. We therefore found that local recurrences of LM commonly arise from subclinical residual disease after surgery. The mutational landscape of recurrent LM/LM melanoma was typical of melanomas arising from chronic sun exposure but also displayed features described in late-stage melanomas.