Genomic analysis and clinical management of adolescent cutaneous melanoma

Abstract

Melanoma in young children is rare; however, its incidence in adolescents and young adults is rising. We describe the clinical course of a 15-year-old female diagnosed with AJCC stage IB non-ulcerated primary melanoma, who died from metastatic disease 4 years after diagnosis despite three lines of modern systemic therapy. We also present the complete genomic profile of her tumour and compare this to a further series of 13 adolescent melanomas and 275 adult cutaneous melanomas. A somatic BRAF^V600E mutation and a high mutational load equivalent to that found in adult melanoma and composed primarily of C>T mutations were observed. A germline genomic analysis alongside a series of 23 children and adolescents with melanoma revealed no mutations in known germline melanoma-predisposing genes. Adolescent melanomas appear to have genomes that are as complex as those arising in adulthood and their clinical course can, as with adults, be unpredictable.

Keywords: BRAF mutation; adolescent melanoma; germline mutation; immunotherapy; ultraviolet radiation.

Figure 1

Clinical timeline of the 15‐year‐old index patient (M_4180). (A) Family pedigree. The proband is indicated with an arrow, ages at diagnosis are shown. (B) Timeline of diagnosis and treatment. (C) New pigmented melanoma in situ appearing in the centre of previous melanoma wide local excision scar. Accompanied dermoscopic image of the in‐situ melanoma prior to further wide local excision (beside). (D) Reflectance confocal microscopy at the dermo‐epidermal level, showing proliferation of dendritic atypical melanocytes. ^aVemurafenib starting dose 960 mg twice a day. ^bDose reduction vemurafenib to 720 mg twice a day. ^cIpilimumab 3 mg/kg every 3 weeks. ^dWhole‐brain radiotherapy 10 Gy in 10 fractions. ^eDabrafenib 150 mg twice a day, trametinib 2 mg once a day.

Figure 2

Radiological evaluation through treatment. (A) 18F‐FDG PET/CT alongside 3D colour reconstruction. Arrows indicate avid FDG tracer uptake in the right axilla, left humeral head, left femoral neck and right iliac crest (blue) as well as widespread liver uptake (red). (B) Post‐contrast T1‐weighted MR images showing tiny enhancing lesions in the left parietal lobe (July 2014) and right amygdala (September 2014). Axial post‐contrast MR images prior to whole‐brain radiotherapy showing multiple and supra‐ and infratentorial lesions with no significant mass effect (October 2014). (C) Cross‐sectional CT images of the liver post‐IV‐contrast in the portal phase. Baseline images show hypodense focal lesions corresponding to segment 1 in the left hepatic lobe (left upper) and the caudal segments of the right hepatic lobe (left lower). On the right, post‐treatment images indicate a partial response in all liver lesions (arrows).

Figure 3

Somatic genomic analyses of adolescent melanoma. (A) Mutational landscape of adolescent melanoma. Driver mutations from the patient described are shown in the first column on the left‐hand side. Remaining cases are from Lu et al. (2015) and indicate the 13 conventional adolescent melanoma patients described within this cohort and for whom genome sequencing data was available. Bar chart across the top panel shows the mutation rate per megabase (Mb) while the right panel shows the mutational frequency in adult cutaneous melanoma found in The Cancer Genome Altas (TCGA; Cancer Genome Atlas Network, 2015), straight line indicates the median number of mutations across all patients. Genes were selected based on those most frequently mutated in The Cancer Genome Atlas (adult) and in Lu et al. (childhood and adolescent; Lu et al., 2015), as well as the loss‐of‐function mutations detected in this 15‐year‐old patient. A number of commonly mutated genes identified in the TCGA melanoma cohort are omitted owing to the absence of mutations of these genes in our adolescent data set (including NRAS,NF1,MAP2K1 and RB1). (B) Cluster plot of mutational frequency of adolescent versus adult cutaneous melanoma. The index patient described is circled in red. (C) Circos plot of somatic changes in the 15‐year‐old patient described. The outermost track shows large copy number gains (red) and losses (green) (Table S8). Middle track shows small insertions and deletions (Table S9). The inner most track shows mutations per Mb (regions marked in red have mutation rates higher than 15 mutations/Mb). Interchromosomal translocations are shown in the centre and were seen in; t(12;6)(q21;q2), t(12;15)(q14;q1), t(16;12)(q23;q2) and t(20;22)(q13;q32) (Table S10).