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A specific amino acid in the Gα 11 subunit of heterotrimeric G proteins was mutated in 32% of primary uveal melanomas and in 57% of uveal melanoma metastases analyzed in this study. This variant was found to activate the mitogen-activated protein kinase pathway. Uveal melanoma is a neoplasm that arises from melanocytes of the choroid plexus, ciliary body, and iris of the eye. 1 Unlike cutaneous melanoma, uveal melanoma lacks mutations in BRAF, NRAS, or KIT 2 – 5 and has characteristic cytogenetic alterations 6 and a strong tendency to metastasize to the liver. 1 , 7 The nevus of Ota, a subtle intradermal proliferation of melanocytes resulting in bluish-gray hyperpigmentation in the sclera and periorbital dermis, is a risk factor for uveal melanoma. 8 In mice, germline mutations that increase the activity of the closely related GTPases, Gα q (V179M) and Gα 11 (I63V), cause dermal hyperpigmentation. 9 The microscopical . . .

Epidermal nevi are common congenital skin lesions with an incidence of 1 in 1,000 people; however, their genetic basis remains elusive. Germline mutations of the FGF receptor 3 (FGFR3) cause autosomal dominant skeletal disorders such as achondroplasia and thanatophoric dysplasia, which can be associated with acanthosis nigricans of the skin. Acanthosis nigricans and common epidermal nevi of the nonorganoid, nonepidermolytic type share some clinical and histological features. We used a SNaPshot multiplex assay to screen 39 epidermal nevi of this type of 33 patients for 11 activating FGFR3 point mutations. In addition, exon 19 of FGFR3 was directly sequenced. We identified activating FGFR3 mutations, almost exclusively at codon 248 (R248C), in 11 of 33 (33%) patients with nonorganoid, nonepidermolytic epidermal nevi. In 4 of these cases, samples from adjacent histologically normal skin could be analyzed, and FGFR3 mutations were found to be absent. Our results suggest that a large proportion of epidermal nevi are caused by a mosaicism of activating FGFR3 mutations in the human epidermis, secondary to a postzygotic mutation in early embryonic development. The R248C mutation appears to be a hot spot for FGFR3 mutations in epidermal nevi.

Christian Hafner and colleagues identify postzygotic HRAS and KRAS mutations as the cause of nevus sebaceous and Schimmelpenning syndrome. Their functional studies suggest that the HRAS p.Gly13Arg alteration, found in 91% of lesions, results in activation of the MAPK and PI3K-Akt signaling pathways. Nevus sebaceous is a common congenital cutaneous malformation. Affected individuals may develop benign and malignant secondary tumors in the nevi during life. Schimmelpenning syndrome is characterized by the association of nevus sebaceous with extracutaneous abnormalities. We report that of 65 sebaceous nevi studied, 62 (95%) had mutations in the HRAS gene and 3 (5%) had mutations in the KRAS gene. The HRAS c.37G>C mutation, which results in a p.Gly13Arg substitution, was present in 91% of lesions. Nonlesional tissues from 18 individuals had a wild-type sequence, confirming genetic mosaicism. The HRAS c.37G>C mutation was also found in 8 of 8 associated secondary tumors. Mosaicism for HRAS c.37G>C and KRAS c.35G>A mutations was found in two individuals with Schimmelpenning syndrome. Functional analysis of HRAS c.37G>C mutant cells showed constitutive activation of the MAPK and PI3K-Akt signaling pathways. Our results indicate that nevus sebaceous and Schimmelpenning syndrome are caused by postzygotic HRAS and KRAS mutations. These mutations may predispose individuals to the development of secondary tumors in nevus sebaceous.

Despite remarkable advances in the genomic characterization of adult melanoma, the molecular pathogenesis of pediatric melanoma remains largely unknown. We analyzed 15 conventional melanomas (CMs), 3 melanomas arising in congenital nevi (CNMs), and 5 spitzoid melanomas (SMs), using various platforms, including whole genome or exome sequencing, the molecular inversion probe assay, and/or targeted sequencing. CMs demonstrated a high burden of somatic single-nucleotide variations (SNVs), with each case containing a TERT promoter (TERT-p) mutation, 13/15 containing an activating BRAF V600 mutation, and >80% of the identified SNVs consistent with UV damage. In contrast, the three CNMs contained an activating NRAS Q61 mutation and no TERT-p mutations. SMs were characterized by chromosomal rearrangements resulting in activated kinase signaling in 40%, and an absence of TERT-p mutations, except for the one SM that succumbed to hematogenous metastasis. We conclude that pediatric CM has a very similar UV-induced mutational spectrum to that found in the adult counterpart, emphasizing the need to promote sun protection practices in early life and to improve access to therapeutic agents being explored in adults in young patients. In contrast, the pathogenesis of CNM appears to be distinct. TERT-p mutations may identify the rare subset of spitzoid melanocytic lesions prone to disseminate.

Key Points Melanomas on the non-glabrous skin (skin outside the palms and soles) can be broadly classified into those that arise on skin with chronic sun-induced damage (CSD melanomas) or those that arise on skin without such damage (non-CSD melanomas). These two melanoma subtypes differ with regard to their age of onset, associated patterns of exposure to UV radiation, association with precursor lesions, clinical and histopathological appearance and somatic mutations. Melanocytic neoplasms range from benign naevi, which are common and have a negligible risk of progressing, to invasive melanomas, which have the potential to metastasize. In between there are intermediate stages that include dysplastic naevi and non-invasive ( in situ ) melanoma. Different melanoma subtypes have different evolutionary trajectories. Non-CSD melanomas commonly arise from benign or dysplastic naevi, whereas CSD melanomas commonly arise from melanoma in situ . As melanomas evolve they do not always pass through discernable evolutionary phases but can seemingly skip individual phases and can even appear without any apparent precursor lesion. Several lines of evidence including TERT promoter mutations in benign or pre-malignant phases of evolution suggest that the cells of common and dysplastic naevi are more proliferative and not entirely senescent, as some models of naevi propose. The relatively stable size of the overall lesion can be explained by the fact that their slow rate of proliferation is offset by cell-attritional factors such as immunosurveillance. Transformation of melanocytes to melanoma is prevented by multiple barriers, which are successively disrupted by genetic alterations. Precursor lesions form when initial mutations induce cell proliferation that is subsequently constrained by cell-autonomous and non-autonomous factors. The expanding cell number increases the probability that descendent cells will acquire additional mutations that override these barriers, enabling evolution to the next phase of progression from a less-evolved precursor lesion. We propose that some melanomas without apparent precursor lesions arise from melanocytes in which the genetic alterations disrupting these barriers already pre-existed before the proliferation-inducing mutation occurred, thereby enabling the neoplasm to skip an evolutionary phase. Melanomas can disseminate in parallel to regional and distant sites to form metastases. Once several metastases have formed, cells from each metastasis continue to seed and reseed other tumours, adding considerable complexity to the diversity of metastatic clones. This Review proposes evolutionary models of tumour progression for melanomas on sun-exposed skin by integrating genetic, epidemiological, clinical and histopathological information. Melanomas on sun-exposed skin are heterogeneous tumours, which can be subtyped on the basis of their cumulative levels of exposure to ultraviolet (UV) radiation. A melanocytic neoplasm can also be staged by how far it has progressed, ranging from a benign neoplasm, such as a naevus, to a malignant neoplasm, such as a metastatic melanoma. Each subtype of melanoma can evolve through distinct evolutionary trajectories, passing through (or sometimes skipping over) various stages of transformation. This Review delineates several of the more common progression trajectories that occur in the patient setting and proposes models for tumour evolution that integrate genetic, histopathological, clinical and biological insights from the melanoma literature.

Some melanocytic tumors can be histologically ambiguous causing diagnostic difficulty, which could lead to overtreatment of benign lesions with an unwarranted psychological distress or undertreatment of malignant cancers. Previously, we demonstrated that significantly decreased miR-211 expression in melanomas compared with melanocytic nevi could accurately discriminate malignant from benign tumors. Herein we show microRNA in situ hybridization for fluorescent detection of miR-211, suitable for paraffin-embedded tissues in 109 primary melanocytic tumors. miR-211 expression was significantly lower in melanomas vs nevi ( P <0.0001), and receiver operating characteristic curve (area under the curve=0.862) accurately discriminated melanomas from nevi with 90% sensitivity and 86.2% specificity. Qualitatively, all dysplastic nevi expressed miR-211 at high (86%) and low (14%) levels, independent of the degree of nuclear atypia. All 35 melanocytic tumors with Spitz morphology expressed miR-211 independent of morphological classification, where clinical follow-up of these patients showed no recurrence at the site or metastasis in mean and median of 3 (ranging 2–5) years. Moreover, a decision tree learning analysis selected age and miR-211 miRNA in situ hybridization as the predictive variables for benign or malignant outcome in 88 patients correctly classified 92% (81 out of 88) of cases as proven by receiver operating characteristic curve (area under the curve=0.9029). These results support miR-211 as a leading miRNA candidate for melanoma diagnosis and miRNA in situ hybridization as a uniquely uncomplicated ancillary test.

Exposing mice with the BRAF (V600E) mutation to levels of ultraviolet radiation that mimic mild sunburn in humans is shown to induce mutations in the tumour suppressor Trp53 (TP53 in humans), accelerating the development of melanoma; these results support the use of sunscreen in individuals at risk of this cancer. Melanoma induction by UV radiation Epidemiological data have linked the incidence of melanoma arising at sun-exposed sites to ultraviolet radiation (UVR), but the specific targets of and the mechanisms by which UVR drives melanoma progression remain unclear. Here Richard Marais and colleagues show that in mice expressing BRAF(V600E), the most common somatic mutation in melanoma, levels of UVR that mimic mild sunburn in humans induce mutations in the tumour suppressor Trp53 and accelerate melanomagenesis. The authors also find that TP53 mutations are linked to evidence of UVR-induced DNA damage in human melanoma. It is accepted that sunscreens protect against squamous cell carcinoma, and this work suggests that they also protect against melanoma. Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear 1 , 2 . The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event 3 . To investigate how UVR accelerates oncogenic BRAF-driven melanomagenesis, we used a BRAF(V600E) mouse model. In mice expressing BRAF(V600E) in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. Here we show that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma, but only provided partial protection. The UVR-exposed tumours showed increased numbers of single nucleotide variants and we observed mutations (H39Y, S124F, R245C, R270C, C272G) in the Trp53 tumour suppressor in approximately 40% of cases. TP53 is an accepted UVR target in human non-melanoma skin cancer, but is not thought to have a major role in melanoma 4 . However, we show that, in mice, mutant Trp53 accelerated BRAF(V600E)-driven melanomagenesis, and that TP53 mutations are linked to evidence of UVR-induced DNA damage in human melanoma. Thus, we provide mechanistic insight into epidemiological data linking UVR to acquired naevi in humans 5 . Furthermore, we identify TP53/Trp53 as a UVR-target gene that cooperates with BRAF(V600E) to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. Our study validates public health campaigns that promote sunscreen protection for individuals at risk of melanoma.

Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a sebaceous nevus and a speckled lentiginous nevus. The coexistence of an epidermal and a melanocytic nevus has been explained by two homozygous recessive mutations, according to the twin spot hypothesis, of which PPK has become a putative paradigm in humans. However, the underlying gene mutations remained unknown. Multiple tissues of six patients with PPK were analyzed for the presence of RAS, FGFR3, PIK3CA, and BRAF mutations using SNaPshot assays and Sanger sequencing. We identified a heterozygous HRAS c.37G>C (p.Gly13Arg) mutation in four patients and a heterozygous HRAS c.182A>G (p.Gln61Arg) mutation in two patients. In each case, the mutations were present in both the sebaceous and the melanocytic nevus. In the latter lesion, melanocytes were identified to carry the HRAS mutation. Analysis of various nonlesional tissues showed a wild-type sequence of HRAS, consistent with mosaicism. Our data provide no genetic evidence for the previously proposed twin spot hypothesis. In contrast, PPK is best explained by a postzygotic-activating HRAS mutation in a multipotent progenitor cell that gives rise to both a sebaceous and a melanocytic nevus. Therefore, PPK is a mosaic RASopathy.

Background: Mutations in GNAQ/11 genes are considered an early event in the development of uveal melanoma that may derive from a pre-existing nevus. The Hippo pathway, by way of YAP activation, rather than MAP kinase, has a role in the oncogenic capacity of GNAQ/11 mutations. Methods: We investigated 16 nevi from 13 human eyes for driver GNAQ/11 mutations using droplet digital PCR and determined whether nevi are clonal by quantifying mutant nevus cell fractions. Immunohistochemistry was performed on 15 nevi to analyse YAP activation. Results: For 15 out of 16 nevi, a GNAQ/11 mutation was detected in the nevus cells albeit at a low frequency with a median of 13%. Nuclear YAP, a transcriptional co-activator in the Hippo tumour-suppressor pathway, was detected in 14/15 nevi. Conclusions: Our analysis suggests that a mutation in GNAQ/11 occurs in a subset of choroidal nevus cells. We hypothesise that GNAQ/11 mutant-driven extracellular mitogenic signalling involving YAP activation leads to accumulation of wild-type nevus cells.

Background The accuracy of melanoma diagnosis continues to challenge the pathology community, even today with sophisticated histopathologic techniques. Melanocytic lesions exhibit significant morphological heterogeneity. While the majority of biopsies can be classified as benign (nevus) or malignant (melanoma) using well-established histopathologic criteria, there exists a cohort for which the prediction of clinical behaviour and invasive or metastatic potential is difficult if not impossible to ascertain on the basis of morphological features alone. Multiple studies have shown that there is significant disagreement between pathologists and even expert dermatopathologists in the diagnosis of this subgroup of difficult melanocytic lesions. Methods A four probe FISH assay was utilized to analyse a cohort of 500 samples including 157 nevus, 176 dysplastic nevus and 167 melanoma specimens. Results Review of the lesions determined the assay identified genetic abnormalities in a total of 83.8% of melanomas, and 1.9% of nevus without atypia, while genetic abnormalities were identified in 6.3%, 6.7%, and 10.3% of nevus identified with mild, moderate and severe atypia, respectively. Conclusions Based on this study, inheritable genetic damage/instability identified by FISH testing is a hallmark of a progressive malignant process, and a valuable diagnostic tool for the identification of high risk lesions.