Massively Parallel Sequencing Analysis of Benign Melanocytic Nevi

Abstract

Aims

Melanocytic nevi are benign lesions of the skin or mucosa, which may constitute non‐obligate precursors of malignant melanoma, particularly when displaying lentiginous and dysplastic features. Here we sought to interrogate the repertoire of somatic genetic alterations in melanocytic nevi.

Methods and Results

DNA extracted from 12 melanocytic nevi and matching normal tissue were separately microdissected and subjected to targeted massively parallel sequencing targeting ≥300 cancer genes. A median of 5.5 (range 1‐12) nonsynonymous somatic mutations was detected, with 10 cases harboring mutually exclusive BRAF V600E (6/12) or NRAS (4/12) clonal hotspot mutations. One of the two cases lacking BRAF and NRAS mutations was a dysplastic nevus harboring a HRAS Q61L hotspot mutation. Analysis of the laser‐capture microdissected components of a nevus synchronously diagnosed with in situ and invasive malignant melanoma revealed a truncal, clonal BRAF V600E mutation, and the acquisition of a CDKN2A homozygous deletion in the invasive component in conjunction with additional clonal mutations affecting NF2, FAT4, and KDR in both in situ and invasive malignant components.

Conclusion

Melanocytic nevi harbor recurrent BRAF V600E or NRAS hotspot mutations with low mutational burdens. Our findings also further validate that progression from nevi to malignant melanoma may be driven by the acquisition of additional genetic alterations, including CDKN2A homozygous deletions.

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