Giant congenital nevi exome sequencing
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PROVIDER: EGAC00001001659 | EGA |
REPOSITORIES: EGA
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Project description:Characterization of the genomic landscape of giant congenital nevi.
| EGAS00001004541 | EGA
Project description:Data Access Committee EGAC00001001509
| EGAC00001001509 | EGA
Project description:Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models permitted the identification of proliferative versus senescent nevus phases and treatments targeting both. These nevi recapitulated the histologic and molecular features of human giant congenital nevi, including the risk of melanoma transformation. Cutaneously delivered MEK, PI3K, and c-KIT inhibitors or proinflammatory squaric acid dibutylester (SADBE) achieved major regressions. SADBE triggered innate immunity that ablated detectable nevocytes, fully prevented melanoma, and regressed human giant nevus xenografts. These findings reveal nevus mechanistic vulnerabilities and suggest opportunities for topical interventions that may alter the therapeutic options for children with congenital giant nevi.
| S-EPMC9237838 | biostudies-literature
Project description:We performed exome sequencing of 77 melanocytic specimens composed of Spitz nevi (n=29), Spitzoid melanomas (n=27), and benign melanocytic nevi (n=21), and compared the results with published melanoma sequencing data. Our study highlights the prominent similarity between Spitzoid and conventional melanomas with similar copy number changes and high and equal numbers of ultraviolet-induced coding mutations affecting similar driver genes. Mutations in MEN1, PRKAR1A, and DNMT3A in Spitzoid melanomas may indicate involvement of the protein kinase A pathway, or a role of DNA methylation in the disease. Other than activating HRAS variants, there were few additional mutations in Spitz nevi, and few copy number changes other than 11p amplification and chromosome 9 deletions. Similarly, there were no large-scale copy number alterations and few somatic alterations other than activating BRAF or NRAS mutations in conventional nevi. A presumed melanoma driver mutation (IDH1Arg132Cys) was revealed in one of the benign nevi. In conclusion, our exome data show significantly lower somatic mutation burden in both Spitz and conventional nevi compared with their malignant counterparts, and high genetic similarity between Spitzoid and conventional melanoma.
| S-EPMC5413430 | biostudies-literature
Project description:Large and giant congenital melanocytic nevi (CMN) are rare melanocytic lesions mostly caused by post-zygotic acquisition of NRAS alteration. However, large/giant CMN may exhibit phenotypic differences among distinct areas patients and in addition, patients differ in features such as presence of multiple CMN or Spilus-like lesions. Overall, 50 fresh-frozen biopsies corresponding to 37 phenotypically characterized areas of large/giant CMNs, 9 satellite lesions, 1 acquired nevus and 3 healthy skin biopsies were analyzed by a multigene panel and RNA sequencing (RNA-seq). Mutational screening showed mutations in 76.2% of large/giant CMN. NRAS mutation was found in 57.1% of cases, and mutations in other genes such as BRAF, KRAS, APC and MET were detected in 14.3% of patients. RNA-seq revealed the fusion transcript ZEB2-ALK and SOX5-RAF1 in large/giant CMN from two patients without point mutations. Both alterations were not detected in unaffected skin and were detected in different affected skin. These findings suggest that large/giant CMN may result from distinct molecular events in addition to NRAS mutations including point mutations and fusions transcripts.
2019-10-24 | GSE120597 | GEO
Project description:Tissue expansion with subsequent adjacent tissue transfer is often the preferred and sometimes the only option for reconstruction of large and giant congenital melanocytic nevi. Successful reconstruction with maximal efficiency and optimal aesthetic outcome requires careful planning of the tissue transfer, which itself requires careful selection of the tissue expander size and positioning. Unfortunately, there is little opportunity to gain experience in these skills due to the rarity of this condition. In situations where there is a rare condition that requires a complex technical procedure with much interoperative decision-making, surgical experience can be supplemented with the use of surgical simulation. In this article, we report on the use of three-dimensional patient imaging, three-dimensional printing, and surgical simulation for planning the reconstruction of large and giant congenital melanocytic nevi. We describe how this technology allows us to simulate multiple different approaches to expander placement and adjacent tissue transfer. We also describe how these simulations can be used to create cutting guides to guide final incision design and reduce intraoperative decision-making. Finally, we discuss how these models can be used to educate patients and families about the process and outcomes of nevus excision and reconstruction.
| S-EPMC10545266 | biostudies-literature
Project description: Not available
| S-EPMC4731027 | biostudies-literature
Project description:BackgroundLarge and giant congenital melanocytic nevi (CMN), benign naevomelanocytic proliferations derived from neural crests, with a projected adult size (PAS) ≥ 20 cm, are connected to a high risk of melanoma and neurocutaneous melanosis. Among several factors, genetic alterations seem to be involved in tumorigenesis. The aim of the present study was to analyse the mutation status of NRAS and BRAF genes in resection specimens from large or giant CMN in a group of Polish patients.Material and methodsThe formalin-fixed, paraffin-embedded resection specimens from 18 patients, fixed in the years of 2006 to 2017, were included in the study. The regions containing the highest load of melanocytes were macrodissected prior to DNA isolation. The NRAS and BRAF mutation status was evaluated using qPCR.ResultsWe detected activating mutations in NRAS gene (codons: 12 and 61) in 7 out of the 18 (38.9%) patients. No BRAF mutations were found.ConclusionOur study, the first molecular analysis of large/giant CMN in Polish patients, supports the hypothesis that NRAS mutation in codon 61 are frequent, recurrent mutations in large/giant CMN. Moreover, we show, for the first time, that NRAS mutations in codon 12 (p.Gly12Asp) can be also detected in giant CMN. The exact role of these genetic alterations in CMN formation remains to be elucidated.
| S-EPMC8603851 | biostudies-literature
Project description:BackgroundCongenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis.ResultsA probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients.ConclusionThe rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients' healthcare and probably has to be democratized notably for complex cases.
| S-EPMC7341591 | biostudies-literature
Project description:Joint Addiction, Aging, and Mental Health Data Access Committee General Research Use Datasets
| PRJNA934661 | ENA