Spitz nevi are benign melanocytic proliferations that can sometimes be clinically and histopathologically difficult to distinguish from melanoma. Agminated Spitz nevi have been reported to arise spontaneously, in association with an underlying nevus spilus, or after radiation or chemotherapy. However, to our knowledge, the genetic mechanism for this eruption has not been described.
We report a case of agminated Spitz nevi arising in a nevus spilus and use exome sequencing to identify a clonal activating point mutation in HRAS (GenBank 3265) (c.37G→C) in the Spitz nevi and underlying nevus spilus. We also identify a secondary copy number increase involving HRAS on chromosome 11p, which occurs during the development of the Spitz nevi.
Conclusions and Relevance
Our results reveal an activating HRAS mutation in a nevus spilus that predisposes to the formation of Spitz nevi. In addition, we demonstrate a copy number increase in HRAS as a “second hit” during the formation of agminated Spitz nevi, which suggests that both multiple Spitz nevi and solitary Spitz nevi may arise through similar molecular pathways. In addition, we describe a unique investigative approach for the discovery of genetic alterations in Spitz nevi.
A and B, Photograph of a large tan patch on the left lower back with 1- to 2-mm hyperpigmented macules and 4- to 6-mm pink papules. C, Pink papule showing plump melanocytes splayed through desmoplastic collagen, consistent with Spitz nevi (hematoxylin-eosin, original magnification ×10). D, Melanocytes with amphophilic cytoplasm in the dermis (hematoxylin-eosin, original magnification ×20).
A, Sanger sequencing of a representative Spitz nevus and adjacent unaffected skin demonstrates a c.37G→C, p.Gly13Arg mutation specific to the lesional tissue. B, Table of HRAS mutations showing the HRAS mutation is present in all 4 Spitz nevi but undetectable in the adjacent normal skin. C, Chromosomal amplifications predicted by SeqGene CNV and displayed with an Integrative Genomics Viewer (http://www.broadinstitute.org/igv/). Both Spitz nevi have a predicted amplification (red bars) over chromosome 11p. D, Dual-color fluorescent in situ hybridization (FISH) with HRAS probe (red signals) and a reference centromeric probe for chromosome 11 (green signals) showing a focus of melanocytes with increased red signal significantly above reference green signals, indicating HRAS amplification (arrows). E, Dual-colored FISH showing a focus of melanocytes with polysomy demonstrated by increased HRAS (red) and centromeric (green) signals in the nucleus (arrows). F, Dual-color FISH showing epidermal keratinocytes and papillary dermal fibroblasts with equivalent red and green signals. G, Sanger sequencing of AciI1-digested DNA from a Spitz nevus, nevus spilus, and the adjacent normal skin demonstrating the HRAS mutation in the nevus spilus and Spitz nevus but not in the normal skin. H, Diagram of 2-hit model of a nevus spilus, with the first hit leading to the macular portion of the nevus spilus and the second hit leading to the formation of Spitz nevi. WT indicates wild type.
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