Abstract 5376: Whole-exome sequencing of acquired nevi identifies novel mechanisms for development and maintenance of benign neoplasms

Abstract

Abstract Background: Acquired melanocytic nevi (AMN) are often mimicking melanoma and ~30% of all melanomas arise within a pre-existing nevus. However, the melanoma transformation rate of each nevus is rare despite the detection of oncogenic mutations BRAF or NRAS mutations in 100% of nevi.Objective: To identify the underlying genetic mechanisms for nevus development.Methods: Nevi, adjacent normal skin, and saliva were sampled from a cross-sectional study. All nevi were clinically, dermoscopically, and histopathologically documented. Using whole-exome sequencing (WES) we assessed the somatic mutational landscape, mutation signatures and copy-number aberrations (CNA) in 30 acquired melanocytic nevi and matching normal skin.Results: In addition to identifying somatic mutations, we confirm the presence of mutational signatures relating to age and ultra-violet radiation (UVR) which mirrors those observed in melanomas of the skin. In matching normal skin of all nevi, we rarely observed the presence of a UVR mutation signature (10% vs. 97% in nevi) despite being exposed to the same amount of UVR as the associated naevus. Instead, we have identified the predominance of defective DNA repair mutation signatures (93%) which we postulate creates the environment for melanocyte transformation sufficient for nevi and perhaps de novo melanoma growth. In copy number aberration (CNA) analysis, in nevi with copy number loss of tumour suppressor genes (TSG), these were balanced by loss of potent oncogenes. Moreover, reticular and non-specific patterned nevi revealed an increased (p<0.0001) number of CNA as compared with globular patterned nevi. Conclusion: The mutation signature data generated in this study confirms that UVR and defective DNA repair mechanism strongly contributes to nevogenesis. The observed copy number changes reflect at a genomic level, the dermoscopic differences of AMN. Lastly, we propose that the balanced loss of TSGs and oncogenes is a protective mechanism of AMN. Citation Format: Mitchell S. Stark, Jean-Marie Tan, Lisa Tom, Kasturee Jagirdar, Duncan Lambie, Helmut Schaider, H. Peter Soyer, Richard A. Sturm. Whole-exome sequencing of acquired nevi identifies novel mechanisms for development and maintenance of benign neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5376.