NGS-Based Analysis of Atypical Deep Penetrating Nevi

Abstract

Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that β-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the β-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found low genetic heterogeneity and a lack of significant associations between specific gene mutations and histopathological features, despite atypical features. Whether the acquisition of an NRAS or IDH1 mutation in an atypical DPN may represent a molecular evolution implying a pathway to melanoma progression should be confirmed in a larger series.

An Atypical Deep Penetrating Nevus With Mutations in Beta Catenin, BRAF V600E , and IDH1 R132C in an 8-Year-Old Boy

“…IDH1 mutations have been described in 38% of atypical DPNs, coexisting with BRAF ( non-V600E ) mutations in 3 cases and with NRAS mutation in 1 case. 3 Interestingly, in this series, the latter case was the only case to show evidence of nodal involvement, although the biological significance of this remains unclear. To date, this case represents the first reported example of an atypical DPN with IDH1 mutation against a background of BRAF V600E mutation.…”

“…10 BRAF V600E mutation has been found in 50% of DPNs 11 and 33% of atypical DPNs. 3 The mutation in CTNNB1 found in this tumor is typical of the missense mutations in exon 3 of CTNNB1 gene found in DPN that lead to genetic activation of the beta-catenin pathway. 11,12 Furthermore, CTNNB1 mutation has been implicated in the morphology of DPN.…”

“…However, it is still unclear to what extent these features correlate with a specific genomic signature or adverse prognosis. 3 In this case report, we describe a deep penetrating melanocytic tumor harboring somatic BRAF V600E , beta catenin, and IDH1 R132C mutations in an 8-year-old boy.…”

“…However, it is still unclear to what extent these features correlate with a specific genomic signature or adverse prognosis. 3…”

Towards diagnostic criteria for malignant deep penetrating melanocytic tumors using single nucleotide polymorphism array and next-generation sequencing

“…The first diagnostic step when encountering a deep penetrating neoplasm should be WHO-pathway confirmation, given the significant clinical implications 10 , for which nuclear β-catenin expression can be used. Previous research reported nuclear βcatenin expression in 98% of genetically unconfirmed DPN 8 and 100% of atypical DPN with CTNNB1 or APC mutations 14 . Our results add that β-catenin IHC might be less reliable in MDPT since three (38%) tumors did not show nuclear β-catenin expression despite 3 Histopathological and SNP array findings in a DPM (Case 9).…”