Spitz
nevi are benign
melanocytic nevi that overlap histopathologically with
melanoma. We previously found copy number increases of chromosome 11p frequently paralleled by mutations in the HRAS oncogene mapping to this region. In this study, we explored mechanisms that inhibit proliferation in the presence of HRAS activation. We analyzed MAP-
kinase activation using immunohistochemistry for phospho-ERK,
cyclin D1, and
microphthalmia transcription factor expression in 17 Spitz
nevi with and 18 Spitz
nevi without 11p copy number increase. We found relatively high levels of phospho-ERK and
cyclin D1 expression suggesting MAP-
kinase pathway activation in both groups of Spitz
nevi. However, Spitz
nevi with 11p copy number increases showed significantly higher levels of
cyclin D1 expression and lower levels of
microphthalmia transcription factor expression suggesting stronger MAP-
kinase pathway activation in this group. Contrasting this apparent activation, the proliferation rate as assessed by Mib1 expression was low in both groups. An analysis of cell-cycle inhibitory
proteins including p16, p21, and p27 showed that the majority of
Spitz nevus cells expressed high levels of p16, with cells of the cases that had increased copy number of 11p expressing significantly higher levels than those of Spitz
nevi with normal copy number of 11p. We propose that in benign
nevi with constitutive activation of the MAP-
kinase pathway, p16 functions as an essential mediator of oncogene-induced senescence preventing progression to
melanoma.