title: The genomic landscape of childhood and adolescent melanoma.
abstract: Despite remarkable advances in the genomic characterization of adult melanoma, the molecular pathogenesis of pediatric melanoma remains largely unknown. We analyzed 15 conventional melanomas (CMs), 3 melanomas arising in congenital nevi (CNMs), and 5 spitzoid melanomas (SMs), using various platforms, including whole genome or exome sequencing, the molecular inversion probe assay, and/or targeted sequencing. CMs demonstrated a high burden of somatic single-nucleotide variations (SNVs), with each case containing a TERT promoter (TERT-p) mutation, 13/15 containing an activating BRAF V600 mutation, and >80% of the identified SNVs consistent with UV damage. In contrast, the three CNMs contained an activating NRAS Q61 mutation and no TERT-p mutations. SMs were characterized by chromosomal rearrangements resulting in activated kinase signaling in 40%, and an absence of TERT-p mutations, except for the one SM that succumbed to hematogenous metastasis. We conclude that pediatric CM has a very similar UV-induced mutational spectrum to that found in the adult counterpart, emphasizing the need to promote sun protection practices in early life and to improve access to therapeutic agents being explored in adults in young patients. In contrast, the pathogenesis of CNM appears to be distinct. TERT-p mutations may identify the rare subset of spitzoid melanocytic lesions prone to disseminate.
authors.affiliation: The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Panduka
authors.initials: P
authors.lastname: Nagahawatte
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: John
authors.initials: J
authors.lastname: Easton
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Seungjae
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Zhifa
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri, USA; Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri, USA; Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri, USA; Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Wyczalkowski
authors.affiliation: Department of Cytogenetics, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Valentine
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Fariba
authors.initials: F
authors.lastname: Navid
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Mulder
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Ruth G
authors.initials: RG
authors.lastname: Tatevossian
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: James
authors.initials: J
authors.lastname: Dalton
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: James
authors.initials: J
authors.lastname: Davenport
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Edmonson
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rusch
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Parker
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Hedlund
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Shurtleff
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Susana
authors.initials: S
authors.lastname: Raimondi
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Vadodaria
authors.initials: V
authors.lastname: Bhavin
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Yergeau
authors.initials: Y
authors.lastname: Donald
authors.affiliation: Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri, USA; Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri, USA; Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri, USA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri, USA; Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri, USA; Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Pounds
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Dyer
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA. Electronic address: alberto.pappo@stjude.org.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pappo
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA. Electronic address: armita.bahrami@stjude.org.
authors.forename: Armita
authors.initials: A
authors.lastname: Bahrami
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005500:Follow-Up Studies; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology; D018332:Nevus, Epithelioid and Spindle Cell / Q000235:genetics / Q000473:pathology; D009508:Nevus, Pigmented / Q000235:genetics / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D019098:Telomerase / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human