title: Genomic Characterization of Dysplastic Nevi Unveils Implications for Diagnosis of Melanoma.
abstract: A well-defined risk factor and precursor for cutaneous melanoma is the dysplastic nevus. These benign tumors represent clonal hyperproliferation of melanocytes that are in a senescent-like state, but with occasional malignant transformation events. To portray the mutational repertoire of dysplastic nevi in patients with the dysplastic nevus syndrome and to determine the discriminatory profiles of melanocytic nevi (including dysplastic nevi) from melanoma, we sequenced exomes of melanocytic nevi including dysplastic nevi (n = 19), followed by a targeted gene panel (785 genes) characterization of melanocytic nevi (n = 46) and primary melanomas (n = 42). Exome sequencing revealed that dysplastic nevi harbored a substantially lower mutational load than melanomas (21 protein-changing mutations versus >100). Known "driver" mutations in genes for melanoma, including CDKN2A, TP53, NF1, RAC1, and PTEN, were not found among any melanocytic nevi sequenced. Additionally, melanocytic nevi including dysplastic nevi showed a significantly lower frequency and a different UV-associated mutational signature. These results show that although melanocytic nevi and dysplastic nevi harbor stable genomes with relatively few alterations, progression into melanomas requires additional mutational processes affecting key tumor suppressors. This study identifies molecular parameters that could be useful for diagnostic platforms.
authors.affiliation: Department of Systems Biology and Department of Biomedical Informatics, Columbia University, New York, New York, USA; Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Melamed
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Iraz T
authors.initials: IT
authors.lastname: Aydin
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Geena Susan
authors.initials: GS
authors.lastname: Rajan
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Phelps
authors.affiliation: Department of Dermatology, Columbia University, New York, New York, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Silvers
authors.affiliation: Department of Systems Biology and Department of Biomedical Informatics, Columbia University, New York, New York, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Emmett
authors.affiliation: Department of Cancer Research, Skin Cancer Center Hornheide, Munster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Brunner
authors.affiliation: Department of Systems Biology and Department of Biomedical Informatics, Columbia University, New York, New York, USA. Electronic address: rr2579@cumc.columbia.edu.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address: julide.celebi@mountsinai.org.
authors.forename: Julide Tok
authors.initials: JT
authors.lastname: Celebi
mesh_terms: D000328:Adult; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004252:DNA Mutational Analysis; D004416:Dysplastic Nevus Syndrome / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D023281:Genomics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D011230:Precancerous Conditions / Q000473:pathology*; D011379:Prognosis; D018570:Risk Assessment; D012494:Sampling Studies; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology