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. 2015 Mar;135(3):816-823.
doi: 10.1038/jid.2014.425. Epub 2014 Sep 30.

The genomic landscape of childhood and adolescent melanoma

Charles Lu  1 , Jinghui Zhang  2 , Panduka Nagahawatte  2 , John Easton  2 , Seungjae Lee  3 , Zhifa Liu  4 , Li Ding  5 , Matthew A Wyczalkowski  1 , Marcus Valentine  6 , Fariba Navid  7 , Heather Mulder  2 , Ruth G Tatevossian  3 , James Dalton  3 , James Davenport  3 , Zhirong Yin  3 , Michael Edmonson  2 , Michael Rusch  2 , Gang Wu  2 , Yongjin Li  2 , Matthew Parker  2 , Erin Hedlund  2 , Sheila Shurtleff  3 , Susana Raimondi  3 , Vadodaria Bhavin  2 , Yergeau Donald  2 , Elaine R Mardis  8 , Richard K Wilson  8 , William E Evans  9 , David W Ellison  3 , Stanley Pounds  4 , Michael Dyer  2 , James R Downing  3 , Alberto Pappo  10 , Armita Bahrami  11
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The genomic landscape of childhood and adolescent melanoma

Charles Lu et al. J Invest Dermatol. 2015 Mar.

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.

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Figures

Figure 1
Figure 1
The clinical and genomic data for 23 pediatric melanomas analyzed by whole genome, whole exome, and/or the molecular inversion probe assay. The mutation rate plot displays the mutation rates in the coding regions for the three subtypes of pediatric melanoma. The gray horizontal line shows the median coding mutation rate in cutaneous melanoma in adults. The mutation spectrum plot in pediatric melanoma demonstrates a high rate of cytidine to thymidine (C–>T) or guanine to adenine (G–>A) transitions in each conventional melanoma sample. The red horizontal line depicts the median rate of transition mutations in melanoma in adults (adapted from data in Hodis et al., 2012). The MC1R variants shown in red font are associated with complete loss of gene function; the variants shown in black font are associated with partial loss of gene function. * SJMEL001020 denoted with an asterisk is an acral melanoma. CTX, translocation; DEL, deletion; MIP, molecular inversion probe assay; SV, structural variation; WES, whole exome sequencing; WGS, whole genome sequencing.
Figure 2
Figure 2
Circos plots showing somatic mutation landscape for the five whole genome sequenced samples. Because of the large number of mutations, only cancer-related genes are labeled in the figure. Inner circle shows interchromosomal (purple) and intrachromosomal (green) translocations. Inner track (orange) denotes area of LOH (loss of heterozygosity). Gray track denotes somatic copy number variations (CNVs) (red=gain; blue=loss). Genes affected by point mutations (single-nucleotide variations (SNVs) and indels) and copy number changes are shown in the outer ring with colors denoting the type of mutation. Truncations and fusion genes caused by translocations are denoted by blue and pink color, respectively. All somatic variants have been validated by targeted deep sequencing.
Figure 3
Figure 3
Comparing the prevalence of copy number variations (CNVs) across the entire chromosomes between adult and pediatric conventional melanoma. (a) The frequency of CNVs in 95 nonacral adult cutaneous melanomas using the single-nucleotide polymorphism (SNP) array data from the study by Hodis et al. (2012) and (b) the frequency of CNVs in 11 pediatric conventional melanomas in our study. The 7q34 locus harboring BRAF was a common region of gain, whereas 9p21 and 10q23.3, spanning CDKN2A and PTEN, were common regions of loss in both adult and pediatric melanomas.
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