UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescents.
Exome sequencing
MC1R
Paediatric melanoma
Rare paediatric tumours
Tumour-normal sequencing
UV-radiation
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Oct 2023
Oct 2023
Historique:
received:
19
05
2023
revised:
24
08
2023
accepted:
30
08
2023
pubmed:
17
9
2023
medline:
17
9
2023
entrez:
16
9
2023
Statut:
ppublish
Résumé
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. 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). 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. 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. Found in Acknowledgement.
Sections du résumé
BACKGROUND
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
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
RESULTS
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
CONCLUSIONS
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
BACKGROUND
Found in Acknowledgement.
Identifiants
pubmed: 37716236
pii: S2352-3964(23)00363-8
doi: 10.1016/j.ebiom.2023.104797
pmc: PMC10511785
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104797Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Outside of submitted work: IBB: Institutional grant from Biontech. O.R. and C.Sc.: grants: Deutsche Forschungsgemeinschaft (DFG), Deutsche Krebshilfe (DKH), European Union (EU), grants to the institution from Illumina and BMS Stiftung Immunonkologie. U.L.S: grants: MSD; support for attending meeting and/or travel: Sun Pharma, Pierre Fabre; participation on a Data Safety Monitoring Board or Advisory Board: MSD, Novartis, Sun Pharma, Almirall, Roche, Sanofi; ADO board member. T.E.: Consulting fees: Bristol-Myers Squibb, MSD, Novartis, Almirall, Hermal, CureVac, Immunocore, Sanofi. S.O.: grants: DFG, Deutsche Luft und Raumfahrt Gesellschaft (DLR), European Union (EU), Bundesministerium für Bildung und Forschung (BMBF), Deutsche Krebshilfe, Bundesministerium für Arbeit und Soziales (BMSA); presentation: Illumina; support for attending meeting and/or travel: Oxford Nanopore Technologies. S.F.: grants: NeraCare, Skyline Dx, Biontech,; speakers honoraria: Kyowa Kirin, Recordati, Takeda Pharmaceuticals.