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.

Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours

“…2a–c). Although its mutation rate in B-ALL, ranging from 0.06 to 0.72 per MB, was 100-fold lower than the average rate in adult (15.8/MB) 8 and pediatric (14.4/MB) 9 skin cancer, T-5 exhibited other features associated with UV-related DNA damage. Specifically, CC>TT dinucleotide mutations were enriched 110-fold in these 8 B-ALLs versus other samples ( P =1.07×10 −7 ), which is consistent with pyrimidine dimer formation.…”

Clinical Outcomes of TP53 Mutations in Cancers

“…Recently, testing recommendations have been broadened to include women with early-onset breast cancer in the absence of family history or BRCA1/ BRCA2 mutations (McCuaig et al 2012), as they would be suspected of carrying de novo TP53 germline mutations (Gonzalez et al 2009). In addition, germline TP53 mutations have now been uncovered in patients who did not fulfill the clinical criteria for LFS testing, but presented with rare pediatric cancers including hypodiploid acute lymphoblastic leukemia (Holmfeldt et al 2013), melanoma (Lu et al 2015), gastric adenocarcinoma (Chang et al 2013), early-onset colorectal cancer (Yurgelun et al 2015), early-onset osteosarcoma (Mirabello et al 2015), or multiple early-onset malignancies (Yamada et al 2009;Chak et al 2015). The wide application of NGS technologies will undoubtedly lead to more such findings and require continued reassessment of the role of TP53 germline variants in cancer predisposition and the need for intense surveillance of mutation carriers and their families (Villani et al 2011).…”

Pigment Cell Skin Neoplasms in Children and Adolescents: Searching Skin Melanoma Diagnostic Markers

“…Что касается диагностики детской и подростковой МК, то допол-нительные затруднения возникают еще и потому, что около половины новообразований у пациентов этих возрастных групп могут не содержать пигмен-та [22]. Обоснованным и своевременно сформулиро-ванным в ряде работ представляется в этой свя-зи мнение, согласно которому лучшее понимание молекулярно-генетических особенностей МК у детей и подростков позволит выработать маркеры для принятия более точных решений [23,24].…”

“…Рациональной основой для такого переноса является распро-страненное клише «меланома -она и есть мела-нома». Вместе с тем очевидные физиологические отличия между лицами из указанных возрастных групп побуждали многих авторов высказывать сомнения в правомерности такого переноса [11,12,24,27]. Приходится, однако, констатировать, что систематический поиск молекулярных марке-ров МК у детей и подростков до сих пор не прово-дился.…”