The Genomic Landscape of Childhood and Adolescent Melanoma

Despite remarkable advances in the genomic characterization of adult melanoma, the molecular pathogenesis of pediatric melanoma remains largely unknown. We analyzed 15 conventional melanomas (CM), 3 melanomas arising in congenital nevi (CNM), and 5 spitzoid melanomas (SM), using various platforms, including whole genome or exome sequencing, molecular inversion probe assay, and/or targeted sequencing. CM demonstrated a high burden of somatic single nucleotide variations (SNV), with each case containing a TERT promoter (TERT-p) mutation, 13/15 containing an activating BRAF V600 mutation, and >80% of the identified SNV consistent with UV damage. By contrast, the 3 CNM contained an activating NRAS Q61 mutation and no TERT-p mutations. SM 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. By contrast, the pathogenesis of CNM appears to be distinct. TERT-p mutations may identify the rare subset of spitzoid melanocytic lesions prone to disseminate.EGA study EGAS00001000901

尽管成人黑色素瘤的基因组表征研究已取得显著进展，但儿童黑色素瘤的分子发病机制仍尚未明确。本研究采用包括全基因组测序、外显子组测序、分子倒置探针（molecular inversion probe assay）分析及靶向测序在内的多种技术平台，对15例常规型黑色素瘤（conventional melanomas, CM）、3例先天性痣源性黑色素瘤（melanomas arising in congenital nevi, CNM）以及5例Spitz型黑色素瘤（spitzoid melanomas, SM）进行了分析。结果显示，CM的体细胞单核苷酸变异（somatic single nucleotide variations, SNV）负荷较高：所有病例均携带TERT启动子（TERT promoter, TERT-p）突变，其中13/15例存在BRAF V600激活突变，且超80%的检出SNV符合紫外线（Ultraviolet, UV）损伤特征。与之形成鲜明对比的是，3例CNM均携带NRAS Q61激活突变，且未检出TERT-p突变。40%的SM病例以可激活激酶信号通路的染色体重排为特征；除1例发生血行转移的SM病例外，其余SM病例均未检出TERT-p突变。本研究结论表明，儿童常规型黑色素瘤的紫外线诱导突变谱与成人对应亚型高度相似，这凸显了在幼年群体中推广防晒措施、以及提升年轻患者获取成人中正在研发的治疗药物的可及性的必要性。与之相反，先天性痣源性黑色素瘤的发病机制似乎截然不同。TERT-p突变或可用于甄别少数易于发生播散的Spitz型黑素细胞病变。EGA研究编号：EGAS00001000901