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We performed multi-omic profiling of epidermal keratinocytes, precancerous actinic keratoses, and squamous cell carcinomas to understand the molecular transitions during skin carcinogenesis. Single-cell mutational analyses showed that most keratinocytes in normal skin had lower mutation burdens than melanocytes and fibroblasts, however keratinocytes with TP53 or NOTCH1 mutations had substantially higher mutation burdens, suggesting that these mutations prime keratinocytes for transformation by increasing their mutation rate. Mutational profiling and spatial transcriptomics on squamous cell carcinomas adjacent to actinic keratoses revealed TERT promoter and CDKN2A mutations emerging in actinic keratoses, whereas additional mutations inactivating ARID2 and activating the MAPK-pathway delineated the transition to squamous cell carcinomas. Spatial variation in gene expression patterns was common in both tumor and immune cells, with high expression of checkpoint molecules at the invasive front of tumors. In conclusion, this study documents key events during the evolution of cutaneous squamous cell carcinoma.
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Acral melanoma is an aggressive type of melanoma with unknown origins. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. We examine exome sequencing data of 139 tissue samples, spanning different progression stages, from 37 patients. We find that 78.4% of the melanomas display clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These complex genomic aberrations are typically shared across all progression stages of individual patients. TERT activating alterations also arise early, whereas MAP-kinase pathway mutations appear later, an inverted order compared to the canonical evolution. The punctuated formation of complex aberrations and early TERT activation suggest a unique mutational mechanism that initiates acral melanoma. The marked intratumoral heterogeneity, especially concerning MAP-kinase pathway mutations, may partly explain the limited success of therapies for this melanoma subtype.
Assuntos
Melanoma , Mutação , Neoplasias Cutâneas , Telomerase , Humanos , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Telomerase/genética , Variações do Número de Cópias de DNA , Evolução Molecular , Masculino , Sequenciamento do Exoma , Feminino , Sistema de Sinalização das MAP Quinases/genéticaRESUMO
NRAS activating mutations are prevalent in melanocytic neoplasia, occurring in a subset of common acquired melanocytic nevi and â¼30% of cutaneous melanomas. In this study, we described a cohort of 7 distinctive melanocytic tumors characterized by activating point mutations in codon 61 of NRAS with amplification of the mutant NRAS allele and shared clinicopathologic features. These tumors occurred predominantly in younger patients, with a median age of 20 years (range, 6-56 years). They presented as papules on the helix of the ear (4 cases) or extremities (3 cases). Microscopically, the tumors were cellular, relatively well-circumscribed, compound, or intradermal proliferations. The tumor cells often extended into the deep reticular dermis and involved the superficial subcutaneous fat in some cases. The melanocytes were epithelioid to spindled with moderate amounts of cytoplasm and conspicuous nucleoli. They were arranged in short plexiform fascicles, nests, and cords. Some cases had occasional pleomorphic and multinucleated melanocytes. Rare dermal mitotic figures were present in all cases. The dermis contained thick collagen bundles and minimal solar elastosis. Follow-up data were available for 5 patients, with a median period of 4.2 years (range, 1-9 years), during which no recurrences or metastases were reported. Our series highlights a clinicopathologically and molecularly distinctive subset of NRAS-mutated tumors with amplification of the mutant NRAS allele.
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GTP Fosfo-Hidrolases , Proteínas de Membrana , Nevo de Células Epitelioides e Fusiformes , Neoplasias Cutâneas , Humanos , GTP Fosfo-Hidrolases/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Proteínas de Membrana/genética , Adulto , Adolescente , Criança , Adulto Jovem , Nevo de Células Epitelioides e Fusiformes/genética , Nevo de Células Epitelioides e Fusiformes/patologia , Melanoma/genética , Melanoma/patologia , Amplificação de Genes , Melanócitos/patologia , Mutação , Nevo Pigmentado/genética , Nevo Pigmentado/patologia , Mutação PuntualRESUMO
Telomerase reverse transcriptase (TERT) promoter mutations (TPMs) are frequently found in different cancer types, including â¼70% of sun-exposed skin melanomas. In melanoma, TPMs are among the earliest mutations and can be present during the transition from nevus to melanoma. However, the specific factors that contribute to the selection of TPMs in certain nevi subsets are not well understood. To investigate this, we analyzed a group of dysplastic nevi (DN) by sequencing genes commonly mutated in melanocytic neoplasms. We examined the relationship between the identified mutations, patient age, telomere length, histological features, and the expression of p16. Our findings reveal that TPMs are more prevalent in DN from older patients and are associated with shorter telomeres. Importantly, these TPMs were not found in nevi with BRAF V600E mutations. Conversely, DN with BRAF V600E mutations were observed in younger patients, had longer telomeres and a higher proportion of p16-positive cells. This suggests that these nevi arrest growth independently of telomere shortening through a mechanism known as oncogene-induced senescence (OIS). These characteristics extend to melanoma-sequencing datasets, where melanomas with BRAF V600E mutations were more likely to have a CDKN2A inactivation, overriding OIS. In contrast, melanomas without BRAF V600E mutations showed a higher frequency of TPMs. Our data imply that TPMs are selected to bypass replicative senescence (RS) in cells that were not arrested by OIS. Overall, our results indicate that a subset of melanocytic neoplasms face constraints from RS, while others encounter OIS and RS. The order in which these barriers are overcome during progression to melanoma depends on the mutational context.
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We describe the first cases of pediatric melanoma with ALK fusion gene arising within giant congenital melanocytic nevi. Two newborn boys presented with large pigmented nodular plaques and numerous smaller satellite nevi. Additional expansile nodules developed within both nevi and invasive melanomas were diagnosed before 10 months of age in both boys. Oncogenic driver mutations in NRAS and BRAF were absent in both cases. Instead, oncogenic ZEB2::ALK fusion genes were identified in both the nevus and melanoma developing within the nevus. In both cases, tumors were noted by ultrasound in utero, demonstrated significant nodularity at birth, and progressed to melanoma in the first year of life suggesting that congenital nevi with ALK fusion genes may behave more aggressively than those with other mutations. As ALK kinase inhibitors are effective against a range of tumors with similar ALK fusion kinases, identifying ALK fusion genes in congenital melanocytic nevi may provide an opportunity for targeted therapy.
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Melanoma , Nevo de Células Epitelioides e Fusiformes , Nevo Pigmentado , Neoplasias Cutâneas , Criança , Humanos , Lactente , Recém-Nascido , Masculino , Quinase do Linfoma Anaplásico/genética , Fusão Gênica/genética , Melanoma/genética , Melanoma/patologia , Nevo Pigmentado/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologiaRESUMO
Spatial transcriptomic technologies, such as the Visium platform, measure gene expression in different regions of tissues. Here, we describe new software, STmut, to visualize somatic point mutations, allelic imbalance, and copy number alterations in Visium data. STmut is tested on fresh-frozen Visium data, formalin-fixed paraffin-embedded (FFPE) Visium data, and tumors with and without matching DNA sequencing data. Copy number is inferred on all conditions, but the chemistry of the FFPE platform does not permit analyses of single nucleotide variants. Taken together, we propose solutions to add the genetic dimension to spatial transcriptomic data and describe the limitations of different datatypes.
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Formaldeído , Neoplasias , Humanos , Transcriptoma , Inclusão em Parafina , Neoplasias/genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Chromosomal rearrangements can initiate and drive cancer progression, yet it has been challenging to evaluate their impact, especially in genetically heterogeneous solid cancers. To address this problem we developed HiDENSEC, a new computational framework for analyzing chromatin conformation capture in heterogeneous samples that can infer somatic copy number alterations, characterize large-scale chromosomal rearrangements, and estimate cancer cell fractions. After validating HiDENSEC with in silico and in vitro controls, we used it to characterize chromosome-scale evolution during melanoma progression in formalin-fixed tumor samples from three patients. The resulting comprehensive annotation of the genomic events includes copy number neutral translocations that disrupt tumor suppressor genes such as NF1, whole chromosome arm exchanges that result in loss of CDKN2A, and whole-arm copy-number neutral loss of homozygosity involving PTEN. These findings show that large-scale chromosomal rearrangements occur throughout cancer evolution and that characterizing these events yields insights into drivers of melanoma progression.
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Aberrações Cromossômicas , Melanoma , Humanos , Variações do Número de Cópias de DNA , Cromossomos , Translocação Genética , Melanoma/genéticaRESUMO
Acral melanoma is an aggressive type of melanoma with unknown origins, arising on the sole, palm, or nail apparatus. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. Our study examined exome sequencing data from 139 tissue samples, spanning different progression stages, collected from 37 patients. We found that 78.4% of the melanomas displayed one or more clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These genomic "hailstorms" were typically shared across all progression stages within individual patients. Genetic alterations known to activate TERT also arose early. By contrast, mutations in the MAP-kinase pathway appeared later during progression, often leading to different tumor areas harboring non-overlapping driver mutations. We conclude that the evolutionary trajectories of acral melanomas substantially diverge from those of melanomas on sun-exposed skin, where MAP-kinase pathway activation initiates the neoplastic cascade followed by immortalization later. The punctuated formation of hailstorms, paired with early TERT activation, suggests a unique mutational mechanism underlying the origins of acral melanoma. Our findings highlight an essential role for telomerase, likely in re-stabilizing tumor genomes after hailstorms have initiated the tumors. The marked genetic heterogeneity, in particular of MAP-kinase pathway drivers, may partly explain the limited success of targeted and other therapies in treating this melanoma subtype.
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Fusion genes involving homologs of protein kinase C (PKC) have been identified in a variety of tumors. We report the clinical and histologic presentation of 51 cutaneous melanocytic neoplasms with a PKC fusion gene (involving PRKCA in 35 cases, PRKCB in 15 cases, and PRKCG in a single case). Most tumors were in young adults (median age, 29.5 years; range, 1-73 years) but some presented in newborns. Histologically, 42 tumors were classified as benign, presenting predominantly as biphasic dermal proliferation (88%) with nests of small melanocytes surrounded by fibrosis with haphazardly arranged spindled and dendritic melanocytes, resembling those reported as "combined blue nevi." Most tumors (60%) were heavily pigmented and in 15%, hyperpigmented epithelioid melanocytes were present at the dermoepidermal junction. Two lesions were paucicellular and showed marked sclerosis. Three tumors, including 2 proliferating nodules, were considered intermediate grade. Six tumors had sheets of atypical melanocytes infiltrating the dermis and were classified as melanomas. Two of the melanomas displayed loss of BAP1 nuclear expression. The median follow-up time was 12 months, with 1 patient alive with metastatic disease and 1 dying of their melanoma. These results suggest that melanocytic tumors with PKC fusion genes have characteristic histopathologic features, which are more similar to blue nevi than to pigmented epithelioid melanocytomas. As is the case with GNA-mutated blue nevi, they can progress to melanomas via BAP1 inactivation and metastasize.
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Melanoma , Nevo Azul , Neoplasias Cutâneas , Recém-Nascido , Adulto Jovem , Humanos , Adulto , Nevo Azul/genética , Biomarcadores Tumorais/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Proteína Quinase C/genéticaRESUMO
TERT promoter mutations (TPMs) are frequently found in different cancer types, including approximately 70% of sun-exposed skin melanomas. In melanoma, TPMs are among the earliest mutations and can be present during the transition from nevus to melanoma. However, the specific factors that contribute to the selection of TPMs in certain nevi subsets are not well understood. To investigate this, we analyzed a group of dysplastic nevi (DN) by sequencing genes commonly mutated in melanocytic neoplasms. We examined the relationship between the identified mutations, patient age, telomere length, histological features, and the expression of p16. Our findings reveal that TPMs are more prevalent in DN from older patients and are associated with shorter telomeres. Importantly, these TPMs were not found in nevi with BRAF V600E mutations. Conversely, DN with BRAF V600E mutations were observed in younger patients, had longer telomeres, and a higher proportion of p16-positive cells. This suggests that these nevi arrest growth independently of telomere shortening through a mechanism known as oncogene-induced senescence (OIS). These characteristics extend to melanoma sequencing data sets, where melanomas with BRAF V600E mutations were more likely to have CDKN2A inactivation, overriding OIS. In contrast, melanomas without BRAF V600E mutations showed a higher frequency of TPMs. Our data imply that TPMs are selected to bypass replicative senescence (RS) in cells that were not arrested by OIS. Overall, our results indicate that a subset of melanocytic neoplasms face constraints from RS, while others encounter OIS and RS. The order in which these barriers are overcome during progression to melanoma depends on the mutational context.
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We report a series of 58 melanocytic tumors that harbor an activating fusion of BRAF, a component of the mitogen-activated protein kinase (MAPK) signaling cascade. Cases were diagnosed as melanocytic nevus (n = 12, 21%), diagnostically ambiguous favor benign (n = 22, 38%), and diagnostically ambiguous concerning for melanoma (n = 12, 21%) or melanoma (n = 12, 21%). Three main histopathologic patterns were observed. The first pattern (buckshot fibrosis) was characterized by large, epithelioid melanocytes arrayed as single cells or "buckshot" within marked stromal desmoplasia. The second pattern (cords in whorled fibrosis) demonstrated polypoid growth with a whorled arrangement of cords and single melanocytes within desmoplasia. The third pattern (spindle-cell fascicles) showed fascicular growth of spindled melanocytes. Cytomorphologic features characteristic of Spitz nevi were observed in most cases (n = 50, 86%). Most of the cases (n = 54, or 93%) showed stromal desmoplasia. Histomorphology alone was not sufficient in distinguishing benign from malignant melanocytic tumors with BRAF fusion gene because the only histopathologic features more commonly associated with a diagnosis of malignancy included dermal mitoses (P = .046) and transepidermal elimination of melanocytes (P = .013). BRAF fusion kinases are targetable by kinase inhibitors and, thus, should be considered as relevant genetic alterations in the molecular workup of melanomas. Recognizing the 3 main histopathologic patterns of melanocytic tumors with BRAF fusion gene will aid in directing ancillary testing.
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Melanoma , Nevo de Células Epitelioides e Fusiformes , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Melanoma/patologia , Nevo de Células Epitelioides e Fusiformes/genética , Fusão Gênica , FibroseRESUMO
Importance: A standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose. Objective: To revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG). Evidence Review: Practicing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0. Findings: The new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low-cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma. Conclusions and Relevance: The implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients.
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Melanoma , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Melanoma/diagnóstico , Melanoma/patologia , Patologistas , Consenso , Instalações de SaúdeRESUMO
OBJECTIVE: To analyze the genetic features of melanocytomas and melanomas of the anterior uvea and assess the value of molecular testing for diagnosis and prognostication. DESIGN: Retrospective case-control study. SUBJECTS: Patients with melanocytoma (n = 16) and melanoma (n = 19) of the anterior uvea. METHODS: Targeted next-generation sequencing was performed on formalin-fixed, paraffin-embedded tumor tissue from anterior uveal melanocytic tumors and correlated with clinicopathologic features. MAIN OUTCOME MEASURES: Presence or absence of accompanying oncogenic alterations beyond GNAQ/GNA11 and their association with histologic features and local recurrence. RESULTS: Hotspot missense mutations in GNAQ/GNA11 were identified in 91% (32/35) of all cases. None of the melanocytomas with or without atypia demonstrated chromosomal imbalances or additional oncogenic variants beyond GNAQ mutation, and none recurred over a median follow-up of 36 months. Additional alterations identified in a subset of melanomas include mutations in BAP1 (n = 3), EIF1AX (n = 4), SRSF2 (n = 1), PTEN (n = 1), and EP300 (n = 1); monosomy 3p (n = 6); trisomy 6p (n = 3); trisomy 8q (n = 2); and an ultraviolet mutational signature (n = 5). Local recurrences were limited to melanomas, all of which demonstrated oncogenic alterations in addition to GNAQ/GNA11 (n = 5). A single melanoma harboring GNAQ and BAP1 mutations and monosomy 3 was the only tumor that metastasized. CONCLUSIONS: In this study, anterior segment uveal melanocytomas did not display oncogenic alterations beyond GNAQ/GNA11. Therefore, they are genetically similar to uveal nevi rather than uveal melanoma based on their molecular features known from the literature. Molecular testing can be performed on borderline cases to aid risk stratification and clinical management decisions.
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Melanoma , Nevo Pigmentado , Neoplasias Cutâneas , Neoplasias Uveais , Humanos , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Análise Mutacional de DNA , Corpo Ciliar/patologia , Estudos Retrospectivos , Estudos de Casos e Controles , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Neoplasias Uveais/diagnóstico , Neoplasias Uveais/genética , Neoplasias Uveais/patologia , Melanoma/patologia , Mutação , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia , Iris/patologiaRESUMO
BACKGROUND: Acral and mucosal melanomas are aggressive subtypes of melanoma, which have a significantly lower burden of somatic mutations than cutaneous melanomas, but more frequent copy number variations, focused gene amplifications, and structural alterations. The landscapes of their genomic alterations remain to be fully characterized. METHODS: We compiled sequencing data of 240 human acral and mucosal melanoma samples from 11 previously published studies and applied a uniform pipeline to call tumor cell content, ploidy, somatic and germline mutations, as well as CNVs, LOH, and SVs. We identified genes that are significantly mutated or recurrently affected by CNVs and implicated in oncogenesis. We further examined the difference in the frequency of recurrent pathogenic alterations between the two melanoma subtypes, correlation between pathogenic alterations, and their association with clinical features. RESULTS: We nominated PTPRJ, mutated and homozygously deleted in 3.8% (9/240) and 0.8% (2/240) of samples, respectively, as a probable tumor suppressor gene, and FER and SKP2, amplified in 3.8% and 11.7% of samples, respectively, as probable oncogenes. We further identified a long tail of infrequent pathogenic alterations, involving genes such as CIC and LZTR1. Pathogenic germline mutations were observed on MITF, PTEN, ATM, and PRKN. We found BRAF V600E mutations in acral melanomas with fewer structural variations, suggesting that they are distinct and related to cutaneous melanomas. Amplifications of PAK1 and GAB2 were more commonly observed in acral melanomas, whereas SF3B1 R625 codon mutations were unique to mucosal melanomas (12.9%). Amplifications at 11q13-14 were frequently accompanied by fusion to a region on chromosome 6q12, revealing a recurrent novel structural rearrangement whose role remains to be elucidated. CONCLUSIONS: Our meta-analysis expands the catalog of driver mutations in acral and mucosal melanomas, sheds new light on their pathogenesis and broadens the catalog of therapeutic targets for these difficult-to-treat cancers.
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Melanoma , Neoplasias Cutâneas , Variações do Número de Cópias de DNA , Genômica , Humanos , Melanoma/patologia , Mutação , Neoplasias Cutâneas/patologia , Fatores de Transcrição/genética , Melanoma Maligno CutâneoRESUMO
IMPORTANCE: Spitz nevi are benign melanocytic neoplasms that classically present in childhood. Isolated Spitz nevi have been associated with oncogenic gene fusions in approximately 50% of cases. The rare agminated variant of Spitz nevi, thought to arise from cutaneous genetic mosaicism, is characterized by development of clusters of multiple lesions in a segmental distribution, which can complicate surgical removal. Somatic single-nucleotide variants in the HRAS oncogene have been described in agminated Spitz nevi, most of which were associated with an underlying nevus spilus. The use of targeted medical therapy for agminated Spitz nevi is not well understood. OBSERVATIONS: A girl aged 30 months presented with facial agminated Spitz nevi that recurred rapidly and extensively after surgery. Owing to the morbidity of further surgery, referral was made to a molecular tumor board. The patient's archival nevus tissue was submitted for extended immunohistochemical analysis and genetic sequencing. Strong ROS1 protein expression was identified by immunohistochemistry. Consistent with this, analysis of whole-genome sequencing data revealed GOPC-ROS1 fusions. These results indicated likely benefit from the oral tyrosine kinase inhibitor crizotinib, which was administered at a dosage of 280 mg/m2 twice daily. An excellent response was observed in all lesions within 5 weeks, with complete flattening after 20 weeks. CONCLUSIONS AND RELEVANCE: Given the response following crizotinib treatment observed in this case, the kinase fusion was believed to be functionally consequential in the patient's agminated Spitz nevi and likely the driver mutational event for growth of her nevi. The repurposing of crizotinib for GOPC-ROS1 Spitz nevi defines a new treatment option for these lesions, particularly in cases for which surgery is relatively contraindicated.
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Crizotinibe , Nevo de Células Epitelioides e Fusiformes , Neoplasias Cutâneas , Proteínas Adaptadoras de Transdução de Sinal , Pré-Escolar , Crizotinibe/uso terapêutico , Feminino , Proteínas da Matriz do Complexo de Golgi , Humanos , Recidiva Local de Neoplasia , Nevo de Células Epitelioides e Fusiformes/diagnóstico , Nevo de Células Epitelioides e Fusiformes/tratamento farmacológico , Nevo de Células Epitelioides e Fusiformes/genética , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genéticaRESUMO
Patients with non-supernumerary ring chromosome 7 syndrome have an increased incidence of hemangiomas, café-au-lait spots, and melanocytic nevi. The mechanism for the increased incidence of these benign neoplasms is unknown. We present the case of a 22-year-old man with ring chromosome 7 and multiple melanocytic nevi. Two nevi, one on the right ear and the other on the right knee, were biopsied and diagnosed as desmoplastic Spitz nevi. Upon targeted next-generation DNA sequencing, both harbored BRAF fusions. Copy number alterations and fluorescence in situ hybridization (FISH) for BRAF suggested that the fusions arose on the ring chromosome 7. Hence, one reason for increased numbers of nevi in patients with non-supernumerary ring chromosome 7 syndrome may be increased likelihood of BRAF fusions, due to the instability of the ring chromosome.
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Transtornos Cromossômicos , Neoplasias da Orelha , Nevo de Células Epitelioides e Fusiformes , Proteínas de Fusão Oncogênica , Proteínas Proto-Oncogênicas B-raf , Cromossomos em Anel , Neoplasias Cutâneas , Adulto , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/metabolismo , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 7/metabolismo , Cromossomos Humanos Par 7/fisiologia , Neoplasias da Orelha/genética , Neoplasias da Orelha/metabolismo , Neoplasias da Orelha/patologia , Humanos , Masculino , Nevo de Células Epitelioides e Fusiformes/genética , Nevo de Células Epitelioides e Fusiformes/metabolismo , Nevo de Células Epitelioides e Fusiformes/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Uveal melanoma (UM) is a currently untreatable form of melanoma with a 50% mortality rate. Characterization of the essential signaling pathways driving this cancer is critical to develop target therapies. Activating mutations in the Gαq signaling pathway at the level of GNAQ, GNA11, or rarely CYSLTR2 or PLCß4 are considered alterations driving proliferation in UM and several other neoplastic disorders. Here, we systematically examined the oncogenic signaling output of various mutations recurrently identified in human tumors. We demonstrate that CYSLTR2 â GNAQ/11 â PLCß act in a linear signaling cascade that, via protein kinase C (PKC), activates in parallel the MAP-kinase and FAK/Yes-associated protein pathways. Using genetic ablation and pharmacological inhibition, we show that the PKC/RasGRP3/MAPK signaling branch is the essential component that drives the proliferation of UM. Only inhibition of the MAPK branch but not the FAK branch synergizes with inhibition of the proximal cascade, providing a blueprint for combination therapy. All oncogenic signaling could be extinguished by the novel GNAQ/11 inhibitor YM-254890, in all UM cells with driver mutation in the Gαq subunit or the upstream receptor. Our findings highlight the GNAQ/11 â PLCß â PKC â MAPK pathway as the central signaling axis to be suppressed pharmacologically to treat for neoplastic disorders with Gαq pathway mutations.
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Melanoma/genética , Oncogenes/fisiologia , Neoplasias Uveais/genética , Animais , Linhagem Celular Tumoral , Quinase 1 de Adesão Focal/fisiologia , Subunidades alfa de Proteínas de Ligação ao GTP/fisiologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Humanos , Sistema de Sinalização das MAP Quinases , Melanoma/patologia , Camundongos , Mutação , Fosfolipase C beta/fisiologia , Proteína Quinase C/fisiologia , Receptores de Leucotrienos/fisiologia , Transdução de Sinais/fisiologia , Neoplasias Uveais/patologiaRESUMO
A subset of Spitz tumors harbor fusions of NTRK3 with ETV6, MYO5A, and MYH9. We evaluated a series of 22 melanocytic tumors in which an NTRK3 fusion was identified as part of the diagnostic workup. Tumors in which NTRK3 was fused to ETV6 occurred in younger patients were predominantly composed of epithelioid melanocytes and were classified by their histopathologic features as Spitz tumors. In contrast, those in which NTRK3 was fused to MYO5A were predominantly composed of spindled melanocytes arrayed in fascicles with neuroid features such as pseudo-Verocay bodies. To further investigate the effects of the fusion kinases ETV6-NTRK3 and MYO5A-NTRK3 in melanocytes, we expressed them in immortalized melanocytes and determined their subcellular localization by immunofluorescence. ETV6-NTRK3 was localized to the nucleus and diffusely within the cytoplasm and caused melanocytes to adopt an epithelioid cytomorphology. In contrast, MYO5A-NTRK3, appeared excluded from the nucleus of melanocytes, was localized to dendrites, and resulted in a highly dendritic cytomorphology. Our findings indicate that ETV6-NTRK3 and MYO5A-NTRK3 have distinct subcellular localizations and effects on cellular morphology.
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Biomarcadores Tumorais/genética , Fusão Gênica , Melanócitos/patologia , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Nevo de Células Epitelioides e Fusiformes/genética , Proteínas de Fusão Oncogênica/genética , Receptor trkC/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Linhagem Celular , Forma Celular , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Nevo de Células Epitelioides e Fusiformes/enzimologia , Nevo de Células Epitelioides e Fusiformes/patologia , Fenótipo , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Adulto JovemRESUMO
Metastasis is generally considered a characteristic of malignant tumors. Herein, we describe a patient with more than one hundred discrete Spitz nevi scattered all over her skin. Molecular analysis from three of the lesions identified a ROS1 fusion oncogene with identical genomic breakpoints, indicating that the nevi arose from a single transformed melanocyte and then disseminated throughout the integument. The demonstration of widespread distribution of a benign tumor with limited proliferative capability indicates that metastatic dissemination is not contingent on full malignant transformation. Thus, eruptive Spitz nevus is a striking example of benign metastasis, demonstrating that metastasis can occur before malignant transformation.
Assuntos
Melanoma/patologia , Nevo de Células Epitelioides e Fusiformes/patologia , Proteínas de Fusão Oncogênica/genética , Neoplasias Cutâneas/secundário , Feminino , Humanos , Melanoma/genética , Pessoa de Meia-Idade , Prognóstico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Neoplasias Cutâneas/genéticaRESUMO
Every cell in the human body has a unique set of somatic mutations, but it remains difficult to comprehensively genotype an individual cell1. Here we describe ways to overcome this obstacle in the context of normal human skin, thus offering a glimpse into the genomic landscapes of individual melanocytes from human skin. As expected, sun-shielded melanocytes had fewer mutations than sun-exposed melanocytes. However, melanocytes from chronically sun-exposed skin (for example, the face) had a lower mutation burden than melanocytes from intermittently sun-exposed skin (for example, the back). Melanocytes located adjacent to a skin cancer had higher mutation burdens than melanocytes from donors without skin cancer, implying that the mutation burden of normal skin can be used to measure cumulative sun damage and risk of skin cancer. Moreover, melanocytes from healthy skin commonly contained pathogenic mutations, although these mutations tended to be weakly oncogenic, probably explaining why they did not give rise to discernible lesions. Phylogenetic analyses identified groups of related melanocytes, suggesting that melanocytes spread throughout skin as fields of clonally related cells that are invisible to the naked eye. Overall, our results uncover the genomic landscapes of individual melanocytes, providing key insights into the causes and origins of melanoma.