RESUMEN
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.
Asunto(s)
Genoma Humano/genética , Genómica , Salud , Melanocitos/citología , Melanoma/genética , Análisis de la Célula Individual , Piel/citología , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Masculino , Melanocitos/metabolismo , Melanocitos/patología , Melanoma/patología , Mutación , Piel/patología , Flujo de TrabajoRESUMEN
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.
Asunto(s)
GTP Fosfohidrolasas , Proteínas de la Membrana , Nevo de Células Epitelioides y Fusiformes , Neoplasias Cutáneas , Humanos , GTP Fosfohidrolasas/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Masculino , Femenino , Persona de Mediana Edad , Proteínas de la Membrana/genética , Adulto , Adolescente , Niño , Adulto Joven , Nevo de Células Epitelioides y Fusiformes/genética , Nevo de Células Epitelioides y Fusiformes/patología , Melanoma/genética , Melanoma/patología , Amplificación de Genes , Melanocitos/patología , Mutación , Nevo Pigmentado/genética , Nevo Pigmentado/patología , Mutación PuntualRESUMEN
BACKGROUND AND AIMS: PKC-fused blue naevi are a recently described group of melanocytic tumours that have distinctive morphological features, including a pigmented epithelioid melanocytoma-like junctional component or a dermal biphasic architecture associating with naevocytoid nests surrounded by dendritic and spindled pigmented melanocytes (so-called 'combined common and blue naevus'). There have been reports of smooth muscle hyperplasia in a hamartoma-like pattern in cases of combined blue naevi without genetic exploration. MATERIALS AND METHODS: Herein, we describe 12 cases of protein kinase C (PKC)-fused blue tumours associated with a co-existing smooth muscle hyperplasia, identified from a total of 98 PKC-fused melanocytic tumours. Archived slides of PKC-fused blue naevi with haematoxylin, eosin and phloxin staining, immunohistochemistry and molecular confirmation of a PKC-fusion by fluorescence in-situ hybridisation (FISH) or RNAseq were re-evaluated for identification of notable smooth muscle hyperplasia. Fifty-one of these slides had already been studied in a previous publication from our group. RESULTS: The hyperplasia ranged from hypertrophic arrector pili muscles to extensive horizontal bundles of disorganised fibres constantly associated and limited within a biphasic dermal melanocytic component. At least one arrector pili muscle was always visible within the tumour, with occasionally direct extension of the hyperplastic fibres from the main muscle body. These muscle fibres were devoid of a PKC-fusion signal by FISH. PKC molecules are involved in the regulation of smooth muscle function, offering an explanatory framework. CONCLUSIONS: These data suggest incorporating smooth muscle hyperplasia as a diagnostic morphological feature of PKC-fused blue melanocytic tumours.
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Hiperplasia , Músculo Liso , Nevo Azul , Proteína Quinasa C , Neoplasias Cutáneas , Humanos , Hiperplasia/patología , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Femenino , Masculino , Adulto , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Nevo Azul/patología , Nevo Azul/genética , Nevo Azul/diagnóstico , Músculo Liso/patología , Persona de Mediana Edad , Adolescente , Adulto Joven , Niño , AncianoRESUMEN
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 y Fusiformes , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Proteínas Proto-Oncogénicas B-raf/genética , Melanoma/patología , Nevo de Células Epitelioides y Fusiformes/genética , Fusión Génica , FibrosisRESUMEN
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 Cutáneas , Recién Nacido , Adulto Joven , Humanos , Adulto , Nevo Azul/genética , Biomarcadores de Tumor/genética , Melanoma/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteína Quinasa C/genéticaRESUMEN
Spitz tumours comprise a spectrum of melanocytic proliferations that share a set of distinct cytological features and molecular pathways. They include benign naevi, intermediate or indeterminate tumours and rare melanomas. Spitz tumours are notorious for the difficulty of distinguishing benign neoplasms with atypical features from melanomas and the related diagnostic uncertainty. Advances in the knowledge of the molecular pathways and genomic aberrations associated with these neoplasms have permitted opportunities for a reduction in the number of uncertain diagnoses and a more objective distinction between Spitz tumours from Spitz-like neoplasms. The presence of a Spitz molecular pathway, such as Harvey rat sarcoma viral oncogene homologue (HRAS) aberrations or kinase fusions, distinguishes a bona fide Spitz neoplasm from Spitz-like naevi or melanomas with conventional driver mutations. Spitz neoplasms with benign histopathological features and, if such testing is performed, benign cytogenetic and molecular findings, are termed Spitz naevi. Spitz neoplasms with frankly malignant histopathological findings or ambiguous microscopic findings associated with genetic or genomic aberrations most in keeping with melanoma are designated as Spitz melanoma. Tumours with microscopic features and genetic/genomic aberrations in between naevi and melanomas are classified as Spitz melanocytoma.
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Melanoma/patología , Nevo de Células Epitelioides y Fusiformes/patología , Neoplasias Cutáneas/patología , Piel/patología , Diagnóstico Diferencial , Humanos , Melanoma/diagnóstico , Melanoma/genética , Nevo de Células Epitelioides y Fusiformes/diagnóstico , Nevo de Células Epitelioides y Fusiformes/genética , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genéticaRESUMEN
The nine pathways to melanoma outlined in the most recent WHO classification of skin tumors attempt to capture the typical evolution of different subtypes of melanoma as governed by cell of origin, mutagenic factors and oncogenic drivers. This pathway-based classification will continue to be refined as we learn more about melanocytic tumor biology. I review the practical application of immunohistochemistry and molecular techniques in the diagnosis of melanocytic tumors in the context of this classification.
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Melanoma , Neoplasias Cutáneas , Humanos , Inmunohistoquímica , Melanoma/diagnóstico , Melanoma/genética , Neoplasias Cutáneas/patologíaRESUMEN
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.
Asunto(s)
Biomarcadores de Tumor/genética , Fusión Génica , Melanocitos/patología , Cadenas Pesadas de Miosina/genética , Miosina Tipo V/genética , Nevo de Células Epitelioides y Fusiformes/genética , Proteínas de Fusión Oncogénica/genética , Receptor trkC/genética , Neoplasias Cutáneas/genética , Adolescente , Adulto , Anciano , Línea Celular , Forma de la Célula , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Nevo de Células Epitelioides y Fusiformes/enzimología , Nevo de Células Epitelioides y Fusiformes/patología , Fenotipo , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Adulto JovenRESUMEN
Activating variants in the platelet-derived growth factor receptor ß gene (PDGFRB) have been associated with Kosaki overgrowth syndrome, infantile myofibromatosis, and Penttinen premature aging syndrome. A recently described phenotype with fusiform aneurysm has been associated with mosaic PDGFRB c.1685A > G p.(Tyr562Cys) variant. Few reports however have examined the vascular phenotypes and mosaic effects of PDGFRB variants. We describe clinical characteristics of two patients with a recurrent mosaic PDGFRB p.(Tyr562Cys) variant identified via next-generation sequencing-based genetic testing. We observed intracranial fusiform aneurysm in one patient and found an additional eight patients with aneurysms and phenotypes associated with PDGFRB-activating variants through literature search. The conditions caused by PDGFRB-activating variants share overlapping features including overgrowth, premature aged skin, and vascular malformations including aneurysms. Aneurysms are progressive and can result in morbidities and mortalities in the absence of successful intervention. Germline and/or somatic testing for PDGFRB gene should be obtained when PDGFRB activating variant-related phenotypes are present. Whole-body imaging of the arterial tree and echocardiography are recommended after diagnosis. Repeating the imaging study within a 6- to 12-month period after detection is reasonable. Finally, further evaluation for the effectiveness and safety profile of kinase inhibitors in this patient population is warranted.
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Aneurisma/genética , Trastornos del Crecimiento/genética , Aneurisma Intracraneal/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Adulto , Envejecimiento Prematuro/genética , Aneurisma/epidemiología , Aneurisma/patología , Niño , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/genética , Trastornos del Crecimiento/epidemiología , Trastornos del Crecimiento/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Aneurisma Intracraneal/epidemiología , Aneurisma Intracraneal/patología , Masculino , Persona de Mediana Edad , Mosaicismo , Fenotipo , Anomalías Cutáneas/epidemiología , Anomalías Cutáneas/genética , Anomalías Cutáneas/patología , Adulto JovenRESUMEN
In daily clinical practice melanocytic nevi are commonly encountered. Traditionally, both benign and malignant melanocytic tumors have been sub-classified by their histopathologic characteristics with differing criteria for malignancy applied to each group. Recently, many of the mutations that initiate nevus formation have been identified and specific sets of mutations are found in different subtypes of nevi. Whereas a single mutation appears sufficient to initiate a nevus, but is not enough to result in melanoma, specific combinations of mutations have been identified in some melanocytic tumors that are regarded to be of low biologic potential. The term "melanocytoma" has recently been proposed by the World Health Organization to describe those tumors that demonstrate genetic progression beyond the single mutations that are found in nevi but are not frankly malignant. Melanocytomas occupy intermediate genetic stages between nevus and melanoma and likely have an increased risk of malignant transformation as compared to nevi. This review provides an update on the broad spectrum of melanocytic nevi and melanocytomas and outlines their key histopathologic and genetic features.
Asunto(s)
Biomarcadores de Tumor/genética , Melanocitos/patología , Mutación , Nevo Pigmentado/genética , Nevo Pigmentado/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Predisposición Genética a la Enfermedad , Humanos , Nevo Pigmentado/clasificación , Fenotipo , Neoplasias Cutáneas/clasificaciónRESUMEN
Melanomas that have histopathologic features that overlap with those of Spitz nevus are referred to as spitzoid melanomas. However, the diagnostic concept is used inconsistently and genomic analyses suggest it is a heterogeneous category. Spitz tumors, the spectrum of melanocytic neoplasms extending from Spitz nevi to their malignant counterpart Spitz melanoma, are defined in the 2018 WHO classification of skin tumors by the presence of specific genetic alterations, such as kinase fusions or HRAS mutations. It is unclear what fraction of "spitzoid melanomas" defined solely by their histopathologic features belong to the category of Spitz melanoma or to other melanoma subtypes. We assembled a cohort of 25 spitzoid melanomas diagnosed at a single institution over an 8-year period and performed high-coverage DNA sequencing of 480 cancer related genes. Transcriptome wide RNA sequencing was performed for select cases. Only nine cases (36%) had genetic alterations characteristic of Spitz melanoma, including HRAS mutation or fusion involving BRAF, ALK, NTRK1, or MAP3K8. The remaining cases were divided into those with an MAPK activating mutation and those without an MAPK activating mutation. Both Spitz melanoma and spitzoid melanomas in which an MAPK-activating mutation could not be identified tended to occur in younger patients on skin with little solar elastosis, infrequently harbored TERT promoter mutations, and had a lower burden of pathogenic mutations than spitzoid melanomas with non-Spitz MAPK-activating mutations. The MAPK-activating mutations identified affected non-V600 residues of BRAF as well as NRAS, MAP2K1/2, NF1, and KIT, while BRAF V600 mutations, the most common mutations in melanomas of the WHO low-CSD category, were entirely absent. While the "spitzoid melanomas" comprising our cohort were enriched for bona fide Spitz melanomas, the majority of melanomas fell outside of the genetically defined category of Spitz melanomas, indicating that histomorphology is an unreliable predictor of Spitz lineage.
Asunto(s)
Melanoma/patología , Nevo de Células Epitelioides y Fusiformes/patología , Neoplasias Cutáneas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Melanoma/genética , Melanoma/metabolismo , Persona de Mediana Edad , Mutación , Nevo de Células Epitelioides y Fusiformes/genética , Nevo de Células Epitelioides y Fusiformes/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Piel/metabolismo , Piel/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Adulto JovenRESUMEN
We report a series of 33 skin tumors harboring a gene fusion of the MAP3K8 gene, which encodes a serine/threonine kinase. The MAP3K8 fusions were identified by RNA sequencing in 28 cases and by break-apart FISH in five cases. Cases in which fusion genes were fully characterized demonstrated a fusion of the 5' part of MAP3K8 comprising exons 1-8 in frame to one of several partner genes at the 3' end. The fusion genes invariably encoded the intact kinase domain of MAP3K8, but not the inhibitory domain at the C-terminus. In 13 (46%) of the sequenced cases, the 3' fusion partner was SVIL. Other recurrent 3' partners were DIP2C and UBL3, with additional fusion partners that occurred only in a single tumor. Clinically, the lesions appeared mainly in young adults (2-59 years of age; median = 18), most commonly involving the lower limbs (55%). Five cases were diagnosed as Spitz nevus, 13 as atypical Spitz tumor, and 15 as malignant Spitz tumor. Atypical and malignant cases more commonly occurred in younger patients. Atypical Spitz tumors and malignant Spitz tumors cases tended to show epidermal ulceration (32%), a dermal component with giant multinucleated cells (32%), and clusters of pigmented cells in the dermis (32%). Moreover, in atypical and malignant cases, a frequent inactivation of CDKN2A (21/26; 77%) was identified either by p16 immunohistochemistry, FISH, or comparative genomic hybridization. Gene expression analysis revealed that MAP3K8 expression levels were significantly elevated compared to a control group of 57 Spitz lesions harboring other known kinase fusions. Clinical follow-up revealed regional nodal involvement in two of six cases, in which sentinel lymph node biopsy was performed but no distant metastatic disease after a median follow-up time of 6 months.
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Quinasas Quinasa Quinasa PAM/genética , Nevo de Células Epitelioides y Fusiformes/genética , Nevo de Células Epitelioides y Fusiformes/patología , Proteínas Proto-Oncogénicas/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica , Adulto JovenRESUMEN
Melanotic schwannoma is a pigmented tumor of peripheral nerve differentiation. Primary cutaneous presentations are extremely rare, as the bulk of melanotic schwannomas tend to develop in paraspinal and axial sites. Tumors arise sporadically and in the setting of the Carney complex. Alterations in the gene encoding protein kinase A regulatory subunit-α (PRKAR1A) underlie most patients with the Carney complex and mediate melanotic schwannoma tumorigenesis. Melanotic schwannomas from noncutaneous sites can locally recur and metastasize widely, leading to a recent proposal to change the nomenclature to "malignant melanotic schwannian tumor." However, the clinicopathologic features of primary cutaneous melanotic schwannomas are relatively unexplored. We present a case of a nodule arising on the vulva of a 34-year-old woman. Microscopically, a dermal-based, heavily pigmented proliferation of plump spindled and epithelioid cells arrayed in nodules and fascicles was seen. Lesional cells stained positively for S100, Melan-A, and BAP1 but were negative for Prkar1α. Next-generation sequencing of a panel of 480 cancer-associated genes revealed that the tumor harbored a PRKAR1A p.S299fs truncating mutation and copy neutral loss of heterozygosity of chromosome 17q, the locus at which PRKAR1A resides. Importantly, no other genetic abnormalities or chromosomal copy number changes were identified. On the basis of combined histopathologic, immunohistochemical, and genetic features, a diagnosis of melanotic schwannoma was rendered. Overall, we present the first clinicopathologic description of a vulvar melanotic schwannoma, review the literature concerning cutaneous presentations of melanotic schwannoma, and propose that melanotic schwannian tumors native to skin may behave more indolently than their noncutaneous counterparts.
Asunto(s)
Neurilemoma/patología , Neoplasias de la Vulva/patología , Adulto , Femenino , Humanos , Melaninas/metabolismo , Neurilemoma/genética , Neurilemoma/metabolismo , Neoplasias de la Vulva/genética , Neoplasias de la Vulva/metabolismoRESUMEN
Well-differentiated papillary mesothelioma is an uncommon mesothelial neoplasm that most frequently arises in the peritoneal cavity of women of reproductive age. Whereas malignant mesothelioma is an aggressive tumor associated with poor outcome, well-differentiated papillary mesothelioma typically exhibits indolent behavior. However, histologically differentiating between these two entities can be challenging, necessitating the development of distinguishing biomarkers. While the genetic alterations that drive malignant mesothelioma have recently been determined, the molecular pathogenesis of well-differentiated papillary mesothelioma is unknown. Here we performed genomic profiling on a cohort of ten well-differentiated papillary mesothelioma of the peritoneum. We identified that all tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, and lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALK that are frequent in malignant mesothelioma. We recently identified that another mesothelial neoplasm, adenomatoid tumor of the genital tract, is genetically defined by somatic missense mutations in the TRAF7 gene, indicating a shared molecular pathogenesis between well-differentiated papillary mesothelioma and adenomatoid tumors. To the best of our knowledge, well-differentiated papillary mesothelioma is the first human tumor type found to harbor recurrent mutations in the CDC42 gene, which encodes a Rho family GTPase. Immunohistochemistry demonstrated intact BAP1 expression in all cases of well-differentiated papillary mesothelioma, indicating that this is a reliable marker for distinguishing well-differentiated papillary mesothelioma from malignant mesotheliomas that frequently display loss of expression. Additionally, all well-differentiated papillary mesothelioma demonstrated robust expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation, similar to that observed in adenomatoid tumors. In contrast, we have previously shown that L1CAM staining is not observed in normal mesothelial cells and malignant mesotheliomas of the peritoneum. Together, these studies demonstrate that well-differentiated papillary mesothelioma is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 that molecularly distinguish this entity from malignant mesothelioma.
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Mesotelioma/genética , Neoplasias Peritoneales/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Proteína de Unión al GTP cdc42/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Mesotelioma/patología , Persona de Mediana Edad , Mutación , Neoplasias Peritoneales/patologíaRESUMEN
Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2. Notably, all tumors lacked alterations in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, TERT (including promoter region), and PTEN, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Glioma/genética , Glioma/radioterapia , Adolescente , Adulto , Astrocitoma/radioterapia , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/radioterapia , Niño , Preescolar , Femenino , Genómica , Homocigoto , Humanos , Masculino , Mutación/genética , Eliminación de Secuencia/genética , Telomerasa/genética , Adulto JovenRESUMEN
Clear cell basal cell carcinoma (BCC) is an unusual variant of BCC. Its pathogenesis, prognosis, and optimal management remain poorly described due to its rarity. This report presents a 51-year-old man with a history of excised BCC and cutaneous squamous cell carcinomas of the face, with multiple recurrent poorly differentiated carcinomas with clear cell changes of the shoulder for which further classification using conventional histologic means was not possible. His tumor tissue was sent to Foundation Medicine for testing, which revealed a high number of pathogenic genomic alterations, including a mutation in PTCH1. He was diagnosed with dedifferentiated BCC and started on vismodegib. He developed lung metastases while receiving vismodegib, and his disease continued to progress while he was undergoing treatment in a phase I clinical trial. Given the high number of pathogenic alterations suggestive of high tumor mutational burden, immunotherapy was considered and off-label authorization was obtained for treatment with a PD-1 antibody (pembrolizumab). He had a dramatic disease response after 4 infusions of pembrolizumab. Molecular testing was instrumental in determining the correct diagnosis and formulating appropriate treatment options for this patient. Molecular profiling of metastatic BCCs and its subtypes is essential to the development of effective targeted therapies and combination approaches.
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Carcinoma Basocelular/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Receptor Patched-1/genética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Carcinoma/genética , Carcinoma/patología , Carcinoma Basocelular/genética , Carcinoma Basocelular/patología , Humanos , Inmunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genéticaRESUMEN
BACKGROUND: The pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known. METHODS: We sequenced 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions. The histopathological spectrum of these areas included unequivocally benign lesions, intermediate lesions, and intraepidermal or invasive melanomas. RESULTS: Precursor lesions were initiated by mutations of genes that are known to activate the mitogen-activated protein kinase pathway. Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorized as intermediate were enriched for NRAS mutations and additional driver mutations. A total of 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, a finding that indicates that these mutations are selected at an unexpectedly early stage of the neoplastic progression. Biallelic inactivation of CDKN2A emerged exclusively in invasive melanomas. PTEN and TP53 mutations were found only in advanced primary melanomas. The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages. Copy-number alterations became prevalent only in invasive melanomas. Tumor heterogeneity became apparent in the form of genetically distinct subpopulations as melanomas progressed. CONCLUSIONS: Our study defined the succession of genetic alterations during melanoma progression, showing distinct evolutionary trajectories for different melanoma subtypes. It identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features. Finally, our study implicated ultraviolet radiation as a major factor in both the initiation and progression of melanoma. (Funded by the National Institutes of Health and others.).
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Evolución Molecular , Melanoma/genética , Mutación , Nevo Pigmentado/genética , Neoplasias Cutáneas/genética , Rayos Ultravioleta/efectos adversos , Variaciones en el Número de Copia de ADN , Progresión de la Enfermedad , Humanos , Melanoma/patología , Nevo Pigmentado/patología , Mutación Puntual , Análisis de Secuencia de ADN , Neoplasias Cutáneas/patologíaRESUMEN
Adenomatoid tumors are the most common neoplasm of the epididymis, and histologically similar adenomatoid tumors also commonly arise in the uterus and fallopian tube. To investigate the molecular pathogenesis of these tumors, we performed genomic profiling on a cohort of 31 adenomatoid tumors of the male and female genital tracts. We identified that all tumors harbored somatic missense mutations in the TRAF7 gene, which encodes an E3 ubiquitin ligase belonging to the family of tumor necrosis factor receptor-associated factors (TRAFs). These mutations all clustered into one of five recurrent hotspots within the WD40 repeat domains at the C-terminus of the protein. Functional studies in vitro revealed that expression of mutant but not wild-type TRAF7 led to increased phosphorylation of nuclear factor-kappa B (NF-kB) and increased expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation. Immunohistochemistry demonstrated robust L1CAM expression in adenomatoid tumors that was absent in normal mesothelial cells, malignant peritoneal mesotheliomas and multilocular peritoneal inclusion cysts. Together, these studies demonstrate that adenomatoid tumors of the male and female genital tract are genetically defined by TRAF7 mutation that drives aberrant NF-kB pathway activation.
Asunto(s)
Tumor Adenomatoide/genética , Neoplasias de los Genitales Femeninos/genética , Neoplasias de los Genitales Masculinos/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Tumor Adenomatoide/metabolismo , Tumor Adenomatoide/patología , Adulto , Anciano , Femenino , Neoplasias de los Genitales Femeninos/metabolismo , Neoplasias de los Genitales Femeninos/patología , Neoplasias de los Genitales Masculinos/metabolismo , Neoplasias de los Genitales Masculinos/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , FN-kappa B/metabolismo , Transducción de Señal/fisiologíaRESUMEN
We present three patients with agminated pyogenic granulomas who experienced significant decrease in size and bleeding with treatment with topical timolol solution with minimal side effects. One patient had complete clinical resolution. For patients with agminated pyogenic granuloma who may otherwise have limited treatment options, timolol is an effective potential solution.