Massively parallel sequencing analysis of benign melanocytic naevi

Abstract

Aims Melanocytic naevi are benign lesions of the skin or mucosa that may constitute non‐obligate precursors of malignant melanoma, particularly when they show lentiginous and dysplastic features. The aim of this study was to investigate the repertoire of somatic genetic alterations in melanocytic naevi. Methods and results DNA extracted from 12 melanocytic naevi and DNA from matching normal tissue were separately microdissected and subjected to targeted massively parallel sequencing of ≥300 cancer genes. A median of 5.5 (range 1–12) non‐synonymous somatic mutations were detected, with 10 cases harbouring 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 naevus harbouring an HRAS Q61L hotspot mutation. Analysis of the laser‐capture microdissected components of a naevus 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 naevi harbour recurrent BRAF V600E or NRAS hotspot mutations with low mutational burdens. Our findings also show that progression from naevi to malignant melanoma may be driven by the acquisition of additional genetic alterations, including CDKN2A homozygous deletions.

Molecular characterisation of metanephric adenomas beyond BRAF: genetic evidence for potential malignant evolution

“…The pattern of molecular alterations seen in the MA with aggressive features is remarkably similar to what has been described in the progression from benign naevus to malignant melanoma. In this oncogene‐induced senescence model, BRAF V600E expression leads to cell cycle arrest via induction of tumour suppressor p16(INK4a) in benign naevi, whereas p16/ CDKN2A is lost during progression to naevus‐associated melanoma 10,24–28 . Pathogenic TERT promoter mutations and MYC overexpression have also been reported as additional selection steps in this context 27,29–32 .…”

Comparison of mutation profiles in primary melanomas and corresponding nodal naevi using next‐generation sequencing

“…concluded that their results are consistent with the two aforementioned theories on the pathogenesis of NN at the molecular biological level. Lozada et al 25 . investigated the repertoire of somatic genetic alterations affecting 300 key cancer genes in CMN, and confirmed the high prevalence of recurrent hotspot mutations affecting BRAF and NRAS .…”

“…Interestingly, Cao et al 24 concluded that their results are consistent with the two aforementioned theories on the pathogenesis of NN at the molecular biological level. Lozada et al 25 investigated the repertoire of somatic genetic alterations affecting 300 key cancer genes in CMN, and confirmed the high prevalence of recurrent hotspot mutations affecting BRAF and NRAS. Furthermore, Shain et al 26 unequivocally benign CMN parts of melanomas harboured BRAF.V600E mutations exclusively, whereas those categorized as intermediate were enriched for NRAS mutations.…”

Maturing papillomatous nevoid melanoma in the scalp mimicking recurrent melanocytic nevus: A case report of previously undescribed subtype of nevoid melanoma

“…3 Homozygous deletion of CDKN2A has been shown in 11.4% and 22.5% of malignant melanomas (n = 40 and n = 61, respectively) 8,9 and in 20.7% of nevoid melanomas (n = 29), 10 but not in benign melanocytic lesions (n = 26). 6,11 The MTAP gene is localized in the same chromosomal region as CDKN2A, and loss of MTAP IHC staining has been proposed as a surrogate marker for CDKN2A co-deletion in various tumors. 12,13 In melanocytic tumors, a decrease in the amount of MTAP protein staining from benign melanocytic nevi to metastatic melanomas has been reported, 14 but the correlation between MTAP IHC and CDKN2A co-deletion has not yet been investigated.…”