Genetics of melanocytic nevi

Abstract

Melanocytic nevi are a benign clonal proliferation of cells expressing the melanocytic phenotype, with heterogeneous clinical and molecular characteristics. In this review, we discuss the genetics of nevi by salient nevi subtypes: congenital melanocytic nevi, acquired melanocytic nevi, blue nevi, and Spitz nevi. While the molecular etiology of nevi has been less thoroughly studied than melanoma, it is clear that nevi and melanoma share common driver mutations. Acquired melanocytic nevi harbor oncogenic mutations in BRAF, which is the predominant oncogene associated with melanoma. Congenital melanocytic nevi and blue nevi frequently harbor NRAS mutations and GNAQ mutations, respectively, while Spitz and atypical Spitz tumors often exhibit HRAS and kinase rearrangements. These initial “driver” mutations are thought to trigger the establishment of benign nevi. After this initial phase of cell proliferation, a senescence program is executed, causing termination of nevi growth. Only upon the emergence of additional tumorigenic alterations, which may provide an escape from oncogene-induced senescence, can malignant progression occur. Here, we review the current literature on the pathobiology and genetics of nevi in the hope that additional studies of nevi promise to inform our understanding of the transition from benign neoplasm to malignancy.

Braf v600 mutation profile of metastatic melanoma in the thrace region of turkey

“…Also, a study by Hughahl et al (22) revealed the association between higher rates of BRAF V600 immunohistochemistry expression and increased tumour thickness, presence of ulceration and higher rates of mitosis. Conversely, several papers have declared that the BRAF V600 mutation has no impact on clinicopathological features or survival (22)(23)(24)(25)(26). Although there was no significant correlation in the present study, the patients with the BRAF V600 mutation were younger than the patients with wild-type BRAF, and NM was detected more commonly in BRAF V600-mutated patients.…”

“…Furthermore, differences between previous studies and the present study may be due to the absence of investigation of LVI and necrosis in many of the above-mentioned studies. However, various molecular alterations accompanying the BRAF V600 mutation may also be features of an ordinary nevus, such as promoter mutations of telomerase reverse transcriptase (TERT) (27,28); mutations in NRAS, PTEN, CDK2NA, STK19, KIT, GNAQ, GNA11 and NF 1 genes (29)(30)(31) or undetected interactions between the BRAF V600 mutation and other signaling pathways (26). Further studies on genotypic and phenotypic alterations in specimens of primary tumours obtained from both metastatic and nonmetastatic patients may provide more information about the impact of the BRAF mutation on prognostic features of melanoma.…”

p15 Expression Differentiates Nevus from Melanoma

“…6,15,16 CDK inhibitors p15 and p16 belong to the INK (inhibitors of kinases) family and act by binding to CDK4, thus preventing its ability to associate with cyclin D, which in turn inhibits CDK4/cyclin Demediated phosphorylation of retinoblastoma-associated protein and prevents G 1e S phase progression. 15,17,18 CDKN2A is part of a gene cluster with CDKN2B, which encodes p15, and therefore the common CDKN2A deletion in human cancer is typically associated with deletion of CDKN2B. 19 The Cancer Genome Atlas analysis of 278 melanomas demonstrated that 93% of melanomas with homozygous deletions of CDKN2A also have homozygous deletions of CDKN2B likely related to the close proximity of these loci on 9p21.…”

Crosstalk in skin: melanocytes, keratinocytes, stem cells, and melanoma

“…Melanocytic nevi (moles) often harbor oncogenic mutations in BRAF and NRAS, which activate an initial phase of cell proliferation (Roh et al 2015). Fortunately nevus growth is usually limited due to a senescence program induced by the oncogenes (Michaloglou et al 2005).…”