UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescentsResearch in context
Summary: Background: Genomic characterisation has led to an improved understanding of adult melanoma. However, the aetiology of melanoma in children is still unclear and identifying the correct diagnosis and therapeutic strategies remains challenging. Methods: Exome sequencing of matched tumour-nor...
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| Language: | English |
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Elsevier
2023-10-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423003638 |
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| author | Alexandra Liebmann Jakob Admard Sorin Armeanu-Ebinger Hannah Wild Michael Abele Axel Gschwind Olga Seibel-Kelemen Christian Seitz Irina Bonzheim Olaf Riess German Demidov Marc Sturm Malou Schadeck Michaela Pogoda Ewa Bien Malgorzata Krawczyk Eva Jüttner Thomas Mentzel Maja Cesen Elke Pfaff Michal Kunc Stephan Forchhammer Andrea Forschner Ulrike Leiter-Stöppke Thomas K. Eigentler Dominik T. Schneider Christopher Schroeder Stephan Ossowski Ines B. Brecht |
| author_facet | Alexandra Liebmann Jakob Admard Sorin Armeanu-Ebinger Hannah Wild Michael Abele Axel Gschwind Olga Seibel-Kelemen Christian Seitz Irina Bonzheim Olaf Riess German Demidov Marc Sturm Malou Schadeck Michaela Pogoda Ewa Bien Malgorzata Krawczyk Eva Jüttner Thomas Mentzel Maja Cesen Elke Pfaff Michal Kunc Stephan Forchhammer Andrea Forschner Ulrike Leiter-Stöppke Thomas K. Eigentler Dominik T. Schneider Christopher Schroeder Stephan Ossowski Ines B. Brecht |
| author_sort | Alexandra Liebmann |
| collection | DOAJ |
| description | Summary: Background: Genomic characterisation has led to an improved understanding of adult melanoma. However, the aetiology of melanoma in children is still unclear and identifying the correct diagnosis and therapeutic strategies remains challenging. Methods: Exome sequencing of matched tumour-normal pairs from 26 paediatric patients was performed to study the mutational spectrum of melanomas. The cohort was grouped into different categories: spitzoid melanoma (SM), conventional melanoma (CM), and other melanomas (OT). Findings: In all patients with CM (n = 10) germline variants associated with melanoma were found in low to moderate melanoma risk genes: in 8 patients MC1R variants, in 2 patients variants in MITF, PTEN and BRCA2. Somatic BRAF mutations were detected in 60% of CMs, homozygous deletions of CDKN2A in 20%, TERTp mutations in 30%. In the SM group (n = 12), 5 patients carried at least one MC1R variant; somatic BRAF mutations were detected in 8.3%, fusions in 25% of the cases. No SM showed a homozygous CDKN2A deletion nor a TERTp mutation. In 81.8% of the CM/SM cases the UV damage signatures SBS7 and/or DBS1 were detected. The patient with melanoma arising in giant congenital nevus (CNM) demonstrated the characteristic NRAS Q61K mutation. Interpretation: UV-radiation and MC1R germline variants are risk factors in the development of conventional and spitzoid paediatric melanomas. Paediatric CMs share genomic similarities with adult CMs while the SMs differ genetically from the CM group. Consistent genetic characterization of all paediatric melanomas will potentially lead to better subtype differentiation, treatment, and prevention in the future. Funding: Found in Acknowledgement. |
| first_indexed | 2024-03-12T00:41:53Z |
| format | Article |
| id | doaj.art-127dec53e6d3434d85e40f46cbf6798e |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-12T00:41:53Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-127dec53e6d3434d85e40f46cbf6798e2023-09-15T04:39:43ZengElsevierEBioMedicine2352-39642023-10-0196104797UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescentsResearch in contextAlexandra Liebmann0Jakob Admard1Sorin Armeanu-Ebinger2Hannah Wild3Michael Abele4Axel Gschwind5Olga Seibel-Kelemen6Christian Seitz7Irina Bonzheim8Olaf Riess9German Demidov10Marc Sturm11Malou Schadeck12Michaela Pogoda13Ewa Bien14Malgorzata Krawczyk15Eva Jüttner16Thomas Mentzel17Maja Cesen18Elke Pfaff19Michal Kunc20Stephan Forchhammer21Andrea Forschner22Ulrike Leiter-Stöppke23Thomas K. Eigentler24Dominik T. Schneider25Christopher Schroeder26Stephan Ossowski27Ines B. Brecht28Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, GermanyPaediatric Hematology and Oncology, University Children’s Hospital Tübingen, Tübingen, GermanyPaediatric Hematology and Oncology, University Children’s Hospital Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, GermanyPaediatric Hematology and Oncology, University Children’s Hospital Tübingen, Tübingen, GermanyInstitute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, GermanySYNLAB MVZ Human Genetics Freiburg GmbH, Freiburg, GermanyInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany; NGS Competence Center Tübingen, Tübingen, GermanyDepartment of Paediatrics, Hematology, Oncology, Medical University of Gdansk, PolandDepartment of Paediatrics, Hematology, Oncology, Medical University of Gdansk, PolandDepartment of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Schleswig-Holstein, GermanyDermatohistopathology Friedrichshafen, Friedrichshafen, GermanyDepartment of Paediatric Haematology and Oncology, University Hospital Ljubljana, Ljubljana, SloveniaHopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, GermanyDepartment of Pathomorphology, Medical University of Gdansk, PolandDepartment of Dermatology, Center for Dermatooncology, University Hospital Tübingen, Tübingen, GermanyDepartment of Dermatology, Center for Dermatooncology, University Hospital Tübingen, Tübingen, GermanyDepartment of Dermatology, Center for Dermatooncology, University Hospital Tübingen, Tübingen, GermanyDepartment of Dermatology, Venereology and Allergology, Charite Universitätsmedizin Berlin, Berlin, GermanyClinic of Paediatrics, Dortmund Municipal Hospital, Dortmund, GermanyInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, GermanyPaediatric Hematology and Oncology, University Children’s Hospital Tübingen, Tübingen, Germany; Corresponding author. Pediatric Hematology and Oncology, University Children's Hospital Tuebingen, Hoppe-Seyler-Str. 1, Tuebingen 72076, Germany.Summary: Background: Genomic characterisation has led to an improved understanding of adult melanoma. However, the aetiology of melanoma in children is still unclear and identifying the correct diagnosis and therapeutic strategies remains challenging. Methods: Exome sequencing of matched tumour-normal pairs from 26 paediatric patients was performed to study the mutational spectrum of melanomas. The cohort was grouped into different categories: spitzoid melanoma (SM), conventional melanoma (CM), and other melanomas (OT). Findings: In all patients with CM (n = 10) germline variants associated with melanoma were found in low to moderate melanoma risk genes: in 8 patients MC1R variants, in 2 patients variants in MITF, PTEN and BRCA2. Somatic BRAF mutations were detected in 60% of CMs, homozygous deletions of CDKN2A in 20%, TERTp mutations in 30%. In the SM group (n = 12), 5 patients carried at least one MC1R variant; somatic BRAF mutations were detected in 8.3%, fusions in 25% of the cases. No SM showed a homozygous CDKN2A deletion nor a TERTp mutation. In 81.8% of the CM/SM cases the UV damage signatures SBS7 and/or DBS1 were detected. The patient with melanoma arising in giant congenital nevus (CNM) demonstrated the characteristic NRAS Q61K mutation. Interpretation: UV-radiation and MC1R germline variants are risk factors in the development of conventional and spitzoid paediatric melanomas. Paediatric CMs share genomic similarities with adult CMs while the SMs differ genetically from the CM group. Consistent genetic characterization of all paediatric melanomas will potentially lead to better subtype differentiation, treatment, and prevention in the future. Funding: Found in Acknowledgement.http://www.sciencedirect.com/science/article/pii/S2352396423003638Paediatric melanomaExome sequencingTumour-normal sequencingMC1RUV-radiationRare paediatric tumours |
| spellingShingle | Alexandra Liebmann Jakob Admard Sorin Armeanu-Ebinger Hannah Wild Michael Abele Axel Gschwind Olga Seibel-Kelemen Christian Seitz Irina Bonzheim Olaf Riess German Demidov Marc Sturm Malou Schadeck Michaela Pogoda Ewa Bien Malgorzata Krawczyk Eva Jüttner Thomas Mentzel Maja Cesen Elke Pfaff Michal Kunc Stephan Forchhammer Andrea Forschner Ulrike Leiter-Stöppke Thomas K. Eigentler Dominik T. Schneider Christopher Schroeder Stephan Ossowski Ines B. Brecht UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescentsResearch in context EBioMedicine Paediatric melanoma Exome sequencing Tumour-normal sequencing MC1R UV-radiation Rare paediatric tumours |
| title | UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescentsResearch in context |
| title_full | UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescentsResearch in context |
| title_fullStr | UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescentsResearch in context |
| title_full_unstemmed | UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescentsResearch in context |
| title_short | UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescentsResearch in context |
| title_sort | uv radiation and mc1r germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescentsresearch in context |
| topic | Paediatric melanoma Exome sequencing Tumour-normal sequencing MC1R UV-radiation Rare paediatric tumours |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423003638 |
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