Whole-Exome Sequencing of Acquired Nevi Identifies Mechanisms for Development and Maintenance of Benign Neoplasms

Abstract

The melanoma transformation rate of an individual nevus is very low despite the detection of oncogenic BRAF or NRAS mutations in 100% of nevi. Acquired melanocytic nevi do, however, mimic melanoma, and approximately 30% of all melanomas arise within pre-existing nevi. Using whole-exome sequencing of 30 matched nevi, adjacent normal skin, and saliva we sought to identify the underlying genetic mechanisms for nevus development. All nevi were clinically, dermoscopically, and histopathologically documented. In addition to identifying somatic mutations, we found mutational signatures relating to UVR mirroring those found in cutaneous melanoma. In nevi we frequently observed the presence of the UVR mutation signature compared with adjacent normal skin (97% vs. 10%, respectively). Copy number aberration analysis showed that for nevi with copy number loss of tumor suppressor genes, this loss was balanced by loss of potent oncogenes. Moreover, reticular and nonspecific patterned nevi showed an increased (P < 0.0001) number of copy number aberrations compared with globular nevi. The mutation signature data generated in this study confirms that UVR strongly contributes to nevogenesis. Copy number changes reflect at a genomic level the dermoscopic differences of acquired melanocytic nevi. Finally, we propose that the balanced loss of tumor suppressor genes and oncogenes is a protective mechanism of acquired melanocytic nevi.

Defining the Molecular Genetics of Dermoscopic Naevus Patterns

“…The findings from this study confirm the mutually exclusive nature of BRAF and NRAS mutations together with a wide range of somatic mutations (30–668 mutations) or 0–9 mutations per megabase present in each melanocytic naevus [69]. Other driver genes detected at a lower prevalence to BRAF V600 include the melanoma-associated genes (e.g., GRIN2A ) and novel genes (e.g., HDAC9 , MYH11 and DCC ) present at a similar mutation frequency to BRAF V600E and BRAF V600K – implying that they most likely occurred at the same time as BRAF during naevus formation [69]. There was a low median somatic mutation burden in the naevi (3 mutations per megabase) in comparison to other UVR-associated cutaneous malignancies such as cutaneous melanoma (38 mutations per megabase) [40] or primary and metastatic cutaneous squamous cell carcinoma (33 mutations to megabase) [70, 71].…”

“…The somatic mutational landscape was determined in globular ( n = 12), reticular ( n = 14) and PG naevi ( n = 4) as well as adjacent normal skin [69]. The findings from this study confirm the mutually exclusive nature of BRAF and NRAS mutations together with a wide range of somatic mutations (30–668 mutations) or 0–9 mutations per megabase present in each melanocytic naevus [69].…”

“…In our recent study, we assessed 30 AMN based upon their dermoscopic pattern using whole-exome sequencing [69]. The somatic mutational landscape was determined in globular ( n = 12), reticular ( n = 14) and PG naevi ( n = 4) as well as adjacent normal skin [69].…”

“…The somatic mutational landscape was determined in globular ( n = 12), reticular ( n = 14) and PG naevi ( n = 4) as well as adjacent normal skin [69]. The findings from this study confirm the mutually exclusive nature of BRAF and NRAS mutations together with a wide range of somatic mutations (30–668 mutations) or 0–9 mutations per megabase present in each melanocytic naevus [69]. Other driver genes detected at a lower prevalence to BRAF V600 include the melanoma-associated genes (e.g., GRIN2A ) and novel genes (e.g., HDAC9 , MYH11 and DCC ) present at a similar mutation frequency to BRAF V600E and BRAF V600K – implying that they most likely occurred at the same time as BRAF during naevus formation [69].…”

Dermatoskopie: Naevi besser verstehen

“…Die Autoren verweisen auf eigene Vorarbeiten, hier wurden 30 erworbene melanozytäre Veränderungen mittels Whole Exome Sequencing untersucht [5]. Die vorher beschriebenen wachsenden Naevi mit globulären Pigmentierungen in der Peripherie der Läsion (n = 4) zeigten zu 100% BRAF V600E Mutationen, retikuläre Naevi (n = 14) zu 67% BRAF V600E/K Mutationen und zu 33% NRAS Mutationen.…”