Molecular basis of melanocytic nevi

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Melanocytic nevi (moles) are exceedingly common and commonly biopsied benign melanocytic neoplasms that are mimics, risk factors, and potential precursors for melanoma, the deadliest of the common forms of skin cancer. Melanocytic neoplasms comprise approximately 50% of all skin biopsies performed. If diagnosed early, melanoma is curable. However, the diagnosis is currently based on histological examination and in up to 10- 25% of cases, pathologists do not agree on the diagnosis. Therefore, novel markers are needed that define both benign and malignant melanocytic neoplasms and could be used for diagnosis and as therapeutic targets. While extensive sequencing efforts have been conducted on melanoma, similar studies on nevi, especially common acquired and dysplastic nevi, the most common pigmented lesions in clinical practice, are limited. The overall hypothesis is that melanocytic nevi show distinct genomic signatures different from melanoma. Utilizing these data will ultimately lead to development of much needed novel objective diagnostic strategies and identification of therapeutic targets. The first aim is to define the genomic landscape of sporadic melanocytic nevi, specifically common acquired and dysplastic nevi. The hypothesis is that nevi show recurrent mutations in a limited number of key genes indicating the existence of molecularly distinct nevus subtypes. Furthermore, the hypothesis is that the genomic landscape correlates with histological features, the current basis for diagnosis of melanocytic tumors. We will perform whole exome and genome sequencing to define main drivers, co-mutations, copy number aberrations, and mutation signatures, and correlate these with detailed clinical and histological features. The second aim is to investigate how germline mutations influence the number and genomic landscape of nevi. Specifically, we will examine a cohort of individuals with Cardio-Facio-Cutaneous syndrome and Costello syndrome caused by germline mutations in various genes of the Ras pathway, the same genes that are critical for melanomagenesis. The hypothesis is that certain germline Ras pathway mutations predispose to the development of nevi but additional co-mutations are required for nevogenesis. We will determine the number of nevi, the strongest risk marker of melanoma, as well as the dermoscopic pattern of nevi, a potential correlate of the germline background. We will collect RASopathy nevi for whole exome and genome sequencing to define genetic events of nevogenesis, including the role of the germline mutation in driving nevogenesis and the presence of potential somatic co-mutations contributing to nevogenesis. By studying sporadic nevi and nevi arising in the setting of germline Ras pathway mutations we will define the drivers and genomic landscape of nevi - the benign counterparts, mimics and potential precursors of melanoma. Ultimately, these studies will lead to identification of much needed novel objective diagnostic markers and therapeutic targets reducing morbidity and mortality related to melanocytic neoplasms.