Sun damage implicated in genetic changes that predispose children and adolescents to melanoma
Despite remarkable advances in the genomic characterization of adult melanoma, the molecular pathogenesis of pediatric melanoma remains largely unknown. The St Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project has found that some adolescent melanomas involve many of the same genetic alterations as adult manifestations of the disease, suggesting that they may respond to the same therapy. The findings are published in the March issue of the Journal of Investigational Dermatology.
The similarities were identified in children and adolescents with conventional melanoma tumors and represent the first genetic evidence that sun damage contributes to melanoma in children and adolescents, as well as adults.
“This study shows that unlike many cancers, conventional melanoma is essentially the same disease in children and adults. That means we need to make it easier for adolescents to access promising therapeutic agents being tried in adults,” commented co-corresponding author Alberto Pappo (St Jude Department of Oncology; TN, USA). “These results also underscore the importance of starting sun protection early and making it a habit for life.”
Distinct genetic alterations were also identified to be associated with other pediatric melanoma subtypes, such as those associated with large congenital nevi and spitzoid tumors. A mutation has been found that may help identify patients with spitzoid tumors who may benefit from aggressive therapy and those who require less intensive treatment to be cured.
It is estimated that 425 patients aged 19 years and under are diagnosed with melanoma in the US each year. While still rare in this age group, incidence of melanoma in young people has demonstrated a 2% increase annually in recent decades, mostly in those aged 15–19 years.
“We were surprised to see that so many of the pediatric melanomas had genetic changes linked to UV damage,” explained co-author Richard K Wilson (The Genome Institute at Washington University School of Medicine in St Louis; MO, USA). “This in-depth look at the genomics of pediatric melanoma is extraordinarily important for diagnosis and for selecting treatments that give young patients the best chances of a cure.”
The research included 23 melanoma patients aged 9 months–19 years; 15 conventional melanomas, three melanomas arising in congenital nevi and five spitzoid melanomas. Researchers utilized whole-genome sequencing and exome sequencing among other methods to compare three different types of melanoma with normal and tumor genomes in order to identify genetic alterations that underlie disease.
Unlike many pediatric cancers, the tumors were seen to include numerous genetic alterations – >90% had genetic changes associated with damage caused by UV light, and >60% had mutations in the BRAF oncogene, the PTEN tumor suppressor gene or the promoter region of TERT. These genetic alterations are found in adult melanoma patients and lead to abnormal cell division and other cancer hallmarks.
In the three patients with the large congenital nevi subtype, mutations in the NRAS oncogene were identified but the disease had no alterations in PTEN. These three individuals all died of their disease.
Cancer caused only one death in the five patients with spitzoid tumors studied and this patient already had widespread disease as well as a TERT promoter mutation. This finding has led to a larger study to examine TERT promoter mutations in order to investigate if they can be used as a marker for spitzoid tumors that will become clinically aggressive. The results are expected soon.
“Until now the genetic basis of pediatric melanoma has been a bit of a mystery,” reported co-corresponding author Armita Bahrami (St Jude Department of Pathology). “With this study, we have established the molecular signatures of the three subtypes of this cancer, signatures that have implications for diagnosis and treatment.”
Source: Lu C, Zhang J, Nagahawatte P et al. The genomic landscape of childhood and adolescent melanoma. J. Invest. Dermatol. 135(3), 816 (2015); St Jude Children’s Research Article news release
